KR20080016952A - Formulation of Nanoparticulate Clopidogrel with Aspirin - Google Patents

Abstract

The present invention is directed to compositions comprising a nanoparticulate clopidogrel and aspirin combination, or salts or derivatives thereof, having improved clopidogrel bioavailability. The nanoparticulate clopidogrel particles, and optionally the nanoparticulate aspirin particles, of the composition have an effective average particle size of less than about 2000 nm and are useful in the prevention and treatment of pathologies induced by platelet aggregation. The clopidogrel and aspirin particles may also be formulated as a controlled release polymeric coating or matrix drug delivery system.

Description

Nanoparticulate clopidogrel and aspirin combination formulations

Cross-Reference of the Related Patent Application

This application is incorporated by reference in its entirety and is incorporated by reference in U.S.C. No. 60 / 689,930, filed June 12, 2005. Insist on priority of § 119 (e).

The present invention relates generally to compounds and compositions useful for the prevention and treatment of pathological states caused by platelet aggregation. More specifically, the present invention relates to nanoparticulate clopidogrel, optionally blended with aspirin in nanoparticulate form (herein referred to as "combination of nanoparticulate clopidogrel and aspirin"), or salts thereof Derivatives, and compositions comprising them. Nanoparticulate clopidogrel, and optionally aspirin, in the formulation composition has an effective average particle size of less than about 2000 nm. In addition, clopidogrel and / or aspirin particles may be coated with any one of polymeric materials for many controlled release and / or delayed release formulations.

A. Clopidogrel  Prior art

Clopidogrel is a platelet aggregation inhibitor. Clopidogrel inhibits ADP-induced platelet aggregation by direct inhibition of ADP binding to adenosine diphosphate (ADP) receptors and subsequent direct inhibition of ADP-mediated activation of the glycoprotein GPIIb / IIa complex. Clopidogrel also inhibits platelet aggregation caused by agonists other than ADP by blocking amplification of platelet activation by released ADP.

The chemical name of clopidogrel bisulfate is methyl (+)-(S) -α- (2-chlorophenyl) -6,7-dihydrothieno [3,2-c] pyridine-5 (4H) -acetate sulfate. (1: 1). The empirical formula of clopidogrel bisulfate is C ₁₆ H ₁₆ ClNO ₂ SH ₂ SO ₄ , and its molecular weight is 419.9. The structural formula is:

Clopidogrel bisulfate is a white to gray powder. It is substantially insoluble in water at neutral pH, but very soluble at pH 1.0. It is also freely soluble in methanol, which is slightly soluble in methylene chloride and is substantially insoluble in ethyl ether.

Clopidogrel bisulfate is commercially available under the trade name PLAVIX® by Bristol-Myers Squibb / Sanofi Pharmaceuticals Partnership (NY, NY). PLAVIX® is administered in oral tablets at a recommended dose of 75 mg once daily. PLAVIX® is a pink, circular, biconvex, debossed film-coated tablet containing 97.875 mg of clopidogrel bisulfate, based on clopidogrel, 75 mg molar equivalent. .

Clopidogrel bisulfate is prescribed for the reduction of thrombotic events such as acute myocardial infarction (MI), acute stroke, or established arterial disease. It has been found to reduce the rate of the combined end point of new ischemic stroke, new MI, and other vascular deaths. In patients with acute coronary syndromes, clopidogrel bisulfate is associated with cardiovascular death, MI, or the rate of complex endpoints of stroke, as well as cardiovascular death, MI, stroke, or refractory ischemia. It has been found to reduce the speed of the combined endpoints.

Clopidogrel is for example a "rotative enantiomer of methyl alpha-5 (4,5,6,7-tetrahydro (3,2-c) thienopyridyl) (2-chlorophenyl) -acetate and US Patent No. 4,847,265 for "A pharmaceutical composition comprising;" U.S. Patent No. 5,576,328 for "Secondary Prevention of Ischemic Events", U.S. Patent No. 5,989,578 for "Combination of Active Ingredients Including Clopidogrel and Anti-Thrombitics", U.S. Patent for "Polymeric Clopidogrel Hydrosulfate Formulations" 6,429,210 and 6,504,030, US Pat. No. 6,635,763 for "Method for Making Clopidogrel," US Pat. Nos. 6,737,411 and 6,800,759 for "Racemination of Clopidogrel and Separation of Enantiomers," and "(S) US Pat. No. 6,858,734 for the preparation of clopidogrel and related compounds. The patent is incorporated herein by reference.

Aspirin, also known as acetylsalicylic acid, is often used as an analgesic (for mild pain and pain), antipyretics (for fever), and anti-inflammatory agents. Aspirin also has an anticoagulant (blood thinning) effect and is used to prevent heart attacks with long-term low-dose.

Aspirin having a CAS number of 50-78-2 is chemically known as 2-acetoxybenzoic acid. Aspirin has the molecular formula C ₉ H ₈ O ₄ and a molecular weight of 180.16. The chemical structure of aspirin is shown below:

Aspirin is colorless or white crystals or white crystalline powder or granules. Aspirin is odorless or almost odorless with a slight acid taste. Aspirin has a melting point of 136 ° C (277 ° F) and a boiling point of 140 ° C (284 ° F). Aspirin can be dissolved in 1 gm of water, 1 gm in alcohol 5-7 gm./ml., 1 gm in chloroform 17 gm./ml., And 1 gm in 20 gm./ml ether. It can be dissolved in a solution of and citrate, and dissolved in an alkali hydroxide and carbonate solution while being decomposed. Aspirin is free acid, acetanilide, aminopyrin, phenazone, hexamine, iron salt, phenobarbitone sodium, quinine salt, potassium and sodium iodine, and alkali hydroxides, carbonates, and stearates Incompatible with Acetylsalicylic acid is stable in dry air, but is gradually hydrolyzed in contact with moisture to form acetic acid and salicylic acid. In alkaline solutions, hydrolysis proceeds rapidly, so that the clear solution formed can consist entirely of acetate and salicylate. Acetylsalicylic acid is rapidly decomposed in ammonium acetate, or an acetate, carbonate, citrate or hydroxide solution of alkali metals.

Aspirin is prescribed as an analgesic for the treatment of mild to moderate pain, as an anti-inflammatory for the treatment of soft tissues and joint inflammation, and as a drug for antipyretics. Aspirin is generally administered in doses of up to 4 gm per day at 300-1000 mg every four hours in adults with pain and fever. For acute polyarthritis rheumatica, administration is generally given 1 gram six times a day and up to 8 grams per day. In the case of rheumatoid arthritis, administration is generally given in 0.5 to 1 gram six times a day and up to 8 grams per day. For the prevention of transient ischemic attacks and the prevention of arterial thrombosis, administration is generally administered from 300 mg to 1200 mg per day in two or three doses.

Aspirin can be used to reduce the likelihood of heart attacks, strokes, or other problems that can occur when blood vessels are blocked by blood clots. Aspirin prevents the formation of dangerous blood clots. Low-dose long-term aspirin irreversibly blocks the production of thromboxane A2 in platelets, creating an inhibitory effect on platelet aggregation, and this blood thinning feature is useful for reducing the incidence of heart attacks Do. Aspirin prepared for this purpose has the strength of 75 mg, 81 mg or 325 mg enteric coated tablets. In addition, high doses of aspirin are given immediately after an acute heart attack.

Various brands of aspirin sold in the United States include, for example, Acuprin 81, Amigesic, Anacin, Caplets, Anacin Maximum Strength, Anacin Tablets, Anaflex 750, Arthritis Pain Ascriptin, Arthritis Pain Formula, Arthritis Strength Bufferin, Arthropan, Aspergum , Aspirin Regimen Bayer Adult Low Dose, Aspirin Regimen Bayer Regular Strength Caplets, Aspir-Low, Aspirtab, Aspirtab-Max, Backache Caplets, Bayer Children's Aspirin, Bayer Select Maximum Strength Backache Pain Relief Formula, Bufferin Caplets, Bufferin Tablets, Buffex, Buffmol , Buffinol Extra, Cama Arthritis Pain Reliever, CMT, Cope, Disalcid, Doan's Regular Strength Tablets, Easprin, Ecotrin Caplets, Ecotrin Tablets, Empirin, Extended-release Bayer 8-Hour, Extra Strength Bayer Arthritis Pain Formula Caplets, Extra Strength Bayer Aspirin Caplets, Extra Strength Bayer Aspirin Tablets, Extra Strength Bayer Plus Caplets, Gensan, Genuine Bayer Aspirin Caplets, Genuine Bayer Aspirin Tablets, Halfprin, Healthprin Adu lt Low Strength, Healthprin Full Strength, Healthprin Half-Dose, Magan, Magnaprin, Marthritic, Maximum Strength Arthritis Foundation Safety Coated Aspirin, Maximum Strength Ascriptin, Maximum Strength Doan's Analgesic Caplets, Mobidin. Mono-Gesic, Norwich Aspirin, P-A-C Revised Formula, Regular Strength Ascriptin, Salflex, Salsitab, Sloprin, St. Joseph Adult Chewable Aspirin, Tricosal, Trilisate, and ZORprin.

Aspirin is described, for example, in US Pat. No. 4,520,09 to "sustained release aspirin formulations" by Dunn; US Patent No. 4,716,042 for "Stabilized Coated Aspirin Tablets" by Blank et al .; US Pat. No. 5,157,030 for "Rapidly Soluble Aspirin Compositions and Methods" by Galat; US Pat. No. 5,723,453 for "stabilized, water-soluble aspirin compositions" by Phykitt; And numerous patents, such as US Reissued Patent No. RE38,576, entitled "Stabilized Aspirin Compositions and Methods for Manufacturing for Oral and Topical Use" by Blahut.

B. Nanoparticulate Active Agents active agent Prior Art Regarding Compositions

The nanoparticulate active agent compositions disclosed for the first time in US Pat. No. 5,145,684 (“'684 Patent“) are poorly soluble, adsorbed onto the surface of a non-crosslinked surface stabilizer. soluble) particles composed of therapeutic or diagnostic drugs. The '684 patent does not describe nanoparticulate compositions of clopidogrel and aspirin combinations.

Methods of preparing nanoparticulate active agent compositions are described, for example, in US Pat. Nos. 5,518,187 and 5,862,999 for "Methods for Grinding Pharmaceutical Substances"; US Patent No. 5,718,388 for "Method of Continuously Grinding Pharmaceutical Substances"; and US Patent No. 5,510,118 for "Methods for Preparing Therapeutic Compositions Comprising Nanoparticles."

Nanoparticulate active agent compositions are also described, for example, in US Pat. No. 5,298,262 for "Use of Ionic Cloud Point Modifiers to Block Particle Accumulation During Sterilization"; US Patent No. 5,302,401 for "Method of Reducing Particle Size Growth During Freeze Drying"; US Patent No. 5,318,767 for "X-Ray Contrast Compositions Useful for Medical Imaging"; US Patent No. 5,326,552 for "Novel Formulations for Nanoparticulate X-Ray Blood Pool Contrast Drugs Using High Molecular Weight Non-ionic Surfactants"; US Patent No. 5,328,404 for "X-Ray Imaging Method Using Iodide Aromatic Propanedioate"; US Patent No. 5,336,507 for "Use to Reduce Nanoparticulate Integration of Charged Phospholipids"; US Patent No. 5,340,564 for "Formulations Containing Olin 10-G for Blocking Particle Aggregation and Enhancing Stability"; US Patent No. 5,346,702 for "Use of Non-Ionic Cloud Point Modifiers to Minimize Nanoparticulate Integration During Sterilization"; US Patent No. 5,349,957 for "Preparation and Magnetic Properties of Very Small Magnetic-Dextran Particles"; US Patent No. 5,352,459 for "Use of Purified Surface Modifiers to Block Particle Accumulation During Sterilization"; US Pat. Nos. 5,399,363 and 5,494,683 for "Surface Modified Anticancer Nanoparticles"; US Patent No. 5,401,492 for "Water Insoluble and Non-Magnetic Manganese Particles as a Magnetic Resonance Enhancement Agent"; US Patent No. 5,429,824 for "Use of Tyloxapol as Nanoparticulate Stabilizer"; US Patent No. 5,447,710 for "Method for Preparing Nanoparticulate X-Ray Blood Pool Contrast Agents Using High Molecular Weight Non-ionic Surfactants; US Patent No. 5,451,393 for "X-Ray Contrast Compositions Useful for Medical Imaging"; US Patent No. 5,466,440 for "Formulations of Oral Gastrointestinal Diagnostic X-Ray Contrast Agents in Combination with Pharmaceutically Acceptable Clays; US Patent No. 5,470,583 for "Method of Making Nanoparticulate Compositions Containing Charged Phospholipids with Reduced Density"; US Patent No. 5,472,683 for "Nanoparticulate Diagnostic Mixed Carbamic Anhydrides as X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging;" US Patent No. 5,500,204 for "Nanoparticulate Diagnostic Dimers as X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging;" US Patent No. 5,518,738 for "Nanoparticulate NSAID Formulations"; US Patent No. 5,521,218 for "Nanoparticulate Iododipamide Derivatives for Use as X-Ray Contrast Drugs; US Patent No. 5,525,328 for "Nanoparticulate Diagnostic Diatrizoxy Ester as X-Ray Contrast Agent for Blood Pool and Lymphatic System Imaging;" US Patent No. 5,543,133 for "Method for Preparing X-Ray Contrast Compositions Comprising Nanoparticles"; US Patent No. 5,552,160 for "Surface Modified NSAID Nanoparticles"; US Patent No. 5,560,931 for "Formulation of Compounds in the Form of Nanoparticulate Dispersions in Digestible Oils or Fatty Acids; US Patent No. 5,565,188 for "Polyalkylene Block Copolymers That Are Surface Modifiers for Nanoparticles"; US Patent No. 5,569,448 for "Sulfated Non-Ionic Block Copolymers That Are Stabilizer Coatings of Nanoparticle Compositions;" US Patent No. 5,571,536 for "Formulation of Compounds in Nanoparticulate Dispersions in Digestible Oils or Fatty Acids"; US Patent No. 5,573,749 for "Nanoparticulate Diagnostic Mixed Carboxy Anhydrides as X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging;" US Patent No. 5,573,750 for "Diagnostic Imaging X-Ray Contrast Agents;" US Patent No. 5,573,783 for "Redispersible Nanoparticulate Film Matrix with Protective Overcoat"; US Pat. No. 5,580,579 for "Site-specific Attachment in the GI tract Using Nanoparticles Stabilized by High Molecular Weight Linear Poly (ethyleneoxide) Polymer"; US Patent No. 5,585,108 for "Formulations of Oral Gastrointestinal Therapeutic Agents in Combination with Pharmaceutically Acceptable Clays"; US Pat. No. 5,587,143 for "Butylene Oxide-Ethylene Oxide Block Copolymer Surfactant as Stabilizer Coatings for Nanoparticulate Compositions;" US Patent No. 5,591,456 for "Naproxen milled with hydroxypropyl cellulose as a dispersion stabilizer"; US Patent No. 5,593,657 for "New Barium Salt Formulations Stabilized with Non-ionic and Anionic Stabilizers"; US Patent No. 5,622,938 for "Sugar Based Surfactants for Nanocrystals"; No. 5,628,981 for "Improved Formulation of Oral Gastrointestinal Diagnostic X-Ray Contrast Agents and Oral Gastrointestinal Therapeutics"; US Pat. No. 5,643,552 for "Carbonic Anhydrides Mixed for Nanoparticulate Diagnostics as X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging; US Patent No. 5,718,388 for "Method of Continuously Grinding Pharmaceutical Substances"; US Patent No. 5,718,919 for "Nanoparticles Containing R (-) Enantiomers of Ibuprofen"; US Patent No. 5,747,001 for "Aerosol comprising Baclomethasone Nanoparticle Dispersion"; US Patent No. 5,834,025 for "Reduction of Negative Physiological Responses Induced by Nanoparticulate Formulations Administered Intravenously"; US Patent No. 6,045,829 for "Nanocrystalline Forms of Human Immunodeficiency Virus (HIV) Protease Inhibitors Using Surface Stabilizers, Cellulose Compounds; US Patent No. 6,068,858 for "Methods for Preparing Nanocrystalline Formulations of Human Immunodeficiency Virus (HIV) Protease Inhibitors Using Surface Stabilizers, Cellulose Compounds; US Patent No. 6,153,225 for "Injectable Formulations of Nanoparticulate Naproxen"; US Patent No. 6,165,506 for "Novel Solid Dosage Forms of Nanoparticulate Naproxen"; US Patent No. 6,221,400 for "Methods for Treating Mammals Using Nanocrystalline Forms of Human Immunodeficiency Virus (HIV) Protease Inhibitors; US Patent No. 6,264,922 for "Nebulized aerosols comprising nanoparticulate dispersions; US Patent No. 6,267,989 for "Method of Blocking Crystal Growth and Particle Accumulation in Nanoparticulate Compositions; US Patent No. 6,270,806 for "Use of PEG-derivatized lipids as surface stabilizers for nanoparticulate compositions"; US Patent No. 6,316,029 for "Oral Solid Dosage Forms That Are Degraded Rapidly"; US Pat. No. 6,375,986 for "Nanoparticulate Compositions for Solid Administration Including Synergistic Combination of Polymeric Surface Stabilizers with Dioctyl Sodium Sulfosuccinate; US Patent No. 6,428,814 for "bioadhesive nanoparticulate compositions comprising cationic surface stabilizers"; US Patent No. 6,431,478 for "Small Milling"; And US Pat. No. 6,432,381 for "Methods for Targeting Drug Delivery to the Upper and / or Lower Gastrointestinal Tract"; US Pat. No. 6,592,903 for "Nanoparticulate Dispersions Containing Synergistic Blending of Polymeric Surface Stabilizers with Dioctyl Sodium Sulfosuccinate; US Pat. No. 6,582,285 for "sanitary wet milling apparatus"; US Patent No. 6,656,504 for "Nanoparticulate compositions comprising amorphous cyclosporin"; US Patent No. 6,742,734 for "System and Method for Milling Materials"; US Patent No. 6,745,962 for "Small Milling and Methods thereof"; US Patent No. 6,811,767 for "Liquid Droplet Aerosols of Nanoparticulate Drugs"; US Patent No. 6,908,626 for "compositions comprising a combination of immediate release and controlled release"; US Pat. No. 6,969,529 for "Nanoparticulate compositions comprising a copolymer of vinyl pyrrolidone and vinyl acetate as surface stabilizer"; And US Pat. No. 6,976,647 for "System and Method for Milling Materials", all of which are specifically incorporated by reference.

In addition, U.S. Patent Publication No. 20020012675 A1 for "Controlled Release Nanoparticulate Compositions" published on January 31, 2002; US Patent Publication No. 20050276974 for "Nanoparticulate Fibrate Formulations"; US Patent Publication No. 20050238725 for "Nanoparticulate compositions with peptides as surface stabilizers"; US Patent Publication No. 20050233001 for "Nanoparticulate megestrol formulations"; US Patent Publication No. 20050147664 for "Compositions Containing Antibodies Targeting Nanoparticulate Active Agent Delivery and Methods of Using the Same; US Patent Publication No. 20050063913 for "New Metalone Composition; US Patent Publication No. 20050042177 for "Novel Compositions of Sildenafil Free Base"; US Patent Publication No. 20050031691 for "gel stabilized nanoparticulate active agent composition"; US Patent Publication No. 20050019412 for "New Glipizide Compositions"; US Patent Publication No. 20050004049 for "New Griseofulpin Compositions"; US Patent Publication No. 20040258758 for "Nanoparticulate Topiramate Formulations;" US Patent Publication No. 20040258757 for "Liquid Dosage Compositions of Stable Nanoparticulate Active Agents"; US Patent Publication No. 20040229038 for "Nanoparticulate Meloxycham Formulations"; US Patent Publication No. 20040208833 for “New Fluticasone Formulations”; US Patent Publication No. 20040195413 for "Method for Milling Compositions and Materials"; US Patent Publication No. 20040156895 for "Solid Dosage Forms Containing Pullulan"; US Patent Publication No. 20040156872 for "New Nimesulide Compositions"; US Patent Publication No. 20040141925 for "New Triamcinolone Compositions"; US Patent Publication No. 20040115134 for "New Nifedipine Composition"; US Patent Publication No. 20040105889 for "Low Density Lipid Dosage Formulations"; US Patent Publication No. 20040105778 for "Gamma Irradiation of Solid Nanoparticulate Active Agents"; US Patent Publication No. 20040101566 for "New Benzoyl Peroxide Compositions"; US Patent Publication No. 20040057905 for "Nanoparticulate Beclomethasone Dipropionate Compositions"; US Patent Publication No. 20040033267 for "Nanoparticulate Compositions of Angiogenesis Inhibitors;" US Patent Publication No. 20040033202 for "Combination of Nanoparticulate Sterol Formulations with New and Old Sterols"; US Patent Publication No. 20040018242 for "Nanoparticulate Nistatin Formulations"; US Patent Publication No. 20040015134 for "Drug Delivery Systems and Methods"; US Patent Publication No. 20030232796 for "Nanoparticulate Policosanol Formulations and Novel Poricosanol Combinations"; US Publication No. 20030215502 for "Quick Dissolution Dosage Formulations with Reduced Friability"; US Publication No. 20030185869 for "Nanoparticulate Compositions Having Lysozyme as Surface Stabilizer"; US Patent Publication No. 20030181411 for "Nanoparticulate Compositions of Mitogen-activated Protein (MAP) Kinase Inhibitors"; US Patent Publication No. 20030137067 for "Compositions Having a Combination of Immediate Release and Controlled Release Features"; US Publication No. 20030108616 for "Nanoparticulate compositions comprising copolymers of vinyl pyrrolidone and vinyl acetate as surface stabilizers"; US Patent Publication No. 20030095928 for "nanoparticulate insulin"; US Patent Publication No. 20030087308 for "High Power Screening Method Using Small Milling or Microflow"; US Patent Publication No. 20030023203 for "Drug Delivery Systems and Methods"; US Patent Publication No. 20020179758 for "Systems and Methods for Milling Materials" and US Publication No. 20010053664 for "Hygiene Wet Milling Devices" describe nanoparticulate active agent compositions and are specifically incorporated by reference.

Amorphous small particle compositions are described, for example, in US Pat. No. 4,783,484 for "particulate compositions and use as antimicrobials"; US Patent No. 4,826,689 for "Methods for Producing Particles of Uniform Size from Water-Insoluble Organic Compounds; US Patent No. 4,997,454 for "Method for Producing Uniformly Sized Particles from Insoluble Compounds"; US Patent No. 5,741,522 for "Uniform, Non-Integrated Porous Particles of Uniform Size and Process for Capturing Gas Bubbles"; US Pat. No. 5,776,496 for "Microporous Particles to Enhance Ultrasonic Back Scatter."

The combination of clopidogrel and aspirin has high therapeutic value in the prevention and treatment of pathologies caused by platelet aggregation. However, since clopidogrel is substantially insoluble in water, effective bioavailability can be a problem. There is a need in the art for a combination formulation of nanoparticulate clopidogrel and aspirin that overcomes these and other problems associated with the use of the combination of clopidogrel and aspirin in the prevention and treatment of diseases caused by platelet aggregation. The present invention satisfies this need.

The present invention relates to a composition comprising clopidogrel, or a salt thereof or a derivative thereof. The present invention also relates to nanoparticulate compositions comprising clopidogrel or salts or derivatives thereof, and to combinations of clopidogrel and aspirin, or compositions comprising salts or derivatives thereof. The composition comprises nanoparticulate clopidogrel, and optionally nanoparticulate aspirin particles, and one or more surface stabilizers adsorbed or associated with the surface of the combined particles of clopidogrel and aspirin. Nanoparticulate clopidogrel particles have an effective average particle size of less than about 2,000 nm. Optionally, the nanoparticulate aspirin particles have an effective average particle size of less than about 2,000 nm.

Conventional clopidogrel bisulfate tablets have limited bioavailability because the drug is substantially insoluble in water. The present invention provides an improved dissolution rate of clopidogrel bisulfate, resulting in increased bioavailability that allows for less administration to provide the same in vivo blood level. do. Additionally, clopidogrel bisulfate can dissolve when exposed to a low pH environment of the stomach and then precipitate out of solution when the drug enters the higher pH region of the adjacent small intestine. This mechanism limits the bioavailability of clopidogrel bisulfate. Application of an enteric coating to clopidogrel bisulfate formulations will prevent solubilization and precipitation from occurring, thus increasing bioavailability. Since clopidogrel bisulfate can cause significant gastric irritation (eg, irritation to the esophagus and stomach), enteric coated formulations are expected to reduce gastric irritation by preventing the drug from dissolving in the stomach. do. Thus, the present invention includes enteric coated clopidogrel compositions, such as, for example, clopidogrel bisulfate, enteric coated nanoparticulate clopidogrel compositions, and enteric coated formulations of nanoparticulate clopidogrel and aspirin particles.

The present invention relates to a composition comprising clopidogrel, nanoparticulate clopidogrel, and a combination of nanoparticulate clopidogrel and aspirin, or salts or derivatives thereof, for the treatment of cardiovascular disease. In addition, the present invention provides nanoparticles in which one or two active ingredients, clopidogrel and aspirin, are coated with one or more polymeric coatings for sustained and / or delayed controlled drug release. Combination particles of particulate clopidogrel and aspirin.

The present invention includes the administration of clopidogrel bisulfate as a multiparticulate formulation that minimizes the high concentration of drug dissolved in the gastro-intestinal tract, which is expected to minimize gastro-intestinal irritation. Accordingly, the present invention also encompasses multiparticulate formulations of clopidogrel bisulfate.

The present invention also includes coadministration of aspirin and clopidogrel to increase the therapeutic outcome of clopidogrel bisulfate. The aspirin component may be a nanoparticulate formulation to increase dissolution but this is not necessary. The aspirin component is preferably enteric coated and multiparticulate to reduce gastrointestinal irritation of aspirin.

The present invention is useful for improving bioavailability and, thus, but not limited to, improving treatment outcomes in all treatments requiring clopidogrel bisulfate and aspirin, including, but not limited to, reducing thrombic events.

The present invention also allows the active ingredient to be released at a sustained and / or delayed release rate for improved and more consistent dissolution rates in the stomach and small intestine, thereby allowing the localization of "hot spots" where high concentrations of drug are localized. A controlled release formulation wherein nanoparticle clopidogrel and aspirin blended particles are coated with one or more polymeric coatings or incorporated into a polymeric material matrix to avoid development.

Enteric-coated pharmaceutical tablet compositions are known. Enteric coated tablets provide resistance to degradation at low pH levels, while releasing drugs at higher pH. Nanoparticulate clopidogrel or a combination particle of clopidogrel and aspirin according to the present invention is preferably enteric coated to delay release of clopidogrel and / or aspirin from orally ingestible dosage forms. In particular, by using an enteric coating, solubilization and precipitation of the clopidogrel activators of the invention are blocked. In addition, gastric irritation is reduced, especially with aspirin in the intestine. Typically most enteric coating polymers can dissolve at pH 5.5 and above, and have a maximum solubility rate at pH above 6.5. Several enteric coated and / or extended release pharmaceutical compositions and methods of making such compositions are disclosed in the art. These may include the active pharmaceutical ingredient as well as additional ingredients such as fillers, buffering agents, binders and wetting agents which are desirable for a given composition. Enteric coatings enable the delivery of the active ingredient to a specific location within the body, such as the lower GI tract, ie the colon or the upper intestine, ie the small intestine, the duodenum. For example, in some embodiments, about 0.05% or less, about 0.5% or less, about or less of the active agent (eg, clopidogrel and / or aspirin) of the enteric coated composition of the present invention relative to the total dose administered to the subject Up to about 1%, up to about 5%, up to about 10%, up to about 20%, or up to about 30% is dissolved in the stomach of the object. In another embodiment, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90 of the active ingredient (eg, clopidogrel and / or aspirin) relative to the total dose administered to the subject At least%, at least about 95%, at least about 97%, or at least about 100% are released from the intestines of the object. The enteric coating may comprise one or more materials that remain in contact during the time the tablet remains in the stomach and do not dissolve and do not decompose or change the structural integrity of the stomach. Preferably, the clopidogrel compounds of the present invention are pharmaceutical , the disclosure of which is incorporated herein by reference in its entirety. Dosage Forms and Drug Delivery Delayed-release methods such as those described in the System , "Modifed-Relaease Dosage Forms and Drug Delivery Systems", Lippincott Williams & Wilkins, 1999, Chapter 8, pp 229-244. As described herein, provided delayed-release formulations are designed to release the drug from the dosage form from any time except immediately after administration. The coating is non-toxic and preferably comprises certain pharmaceutically acceptable enteric polymers which are markedly soluble in intestinal fluids but are substantially insoluble in gastric fluids. A wide range of other polymeric materials are known to have such solubility characteristics.

Combination formulations of nanoparticulate clopidogrel with aspirin are also formulated in an intravenous solution for immediate administration prior to or during a cardiac event, as well as for immediate onset of drug treatment action, for ease of improved administration. Can be.

Preferred dosage forms of the invention are solid dosage forms, although any pharmaceutically acceptable dosage form may be used.

Another embodiment of the present invention comprises a combination of nanoparticulate clopidogrel and aspirin, or salts or derivatives thereof, and one or more surface stabilizers, pharmaceutically acceptable carriers, as well as any desired excipients It relates to a pharmaceutical composition.

Another embodiment of the invention relates to a combination composition of nanoparticulate clopidogrel and aspirin further comprising at least one compound useful for the prevention and treatment of diseases caused by platelet aggregation, preferably cardiovascular disease.

The present invention also provides a method of preparing a combination composition of the nanoparticulate clopidogrel and aspirin of the present invention. The method comprises contacting the combination of nanoparticulate clopidogrel and aspirin, or a salt or derivative thereof, with at least one surface stabilizer for a time and under conditions sufficient to provide a stabilized nanoparticulate clopidogrel and aspirin combination composition. Include.

The present invention also provides for the prevention and treatment of diseases caused by platelet aggregation, preferably but not limited to, including but not limited to the use of the combination composition of the novel nanoparticulate clopidogrel and aspirin disclosed herein. It relates to a treatment method comprising. The method comprises the step of administering to the subject a therapeutically effective amount of a nanoparticulate clopidogrel and aspirin, or a salt or derivative thereof thereof. Other methods of treatment using the nanoparticulate compositions of the invention are known to those skilled in the art.

The above summary of the present invention, the following brief description of the drawings and the detailed description of the invention are by way of example only, and are intended to provide further details of the claimed invention. Other objects, advantages and novel features will be apparent to those skilled in the art from the following detailed description of the invention.

Detailed description of the invention

I. Nanoparticle Type Clopidogrel  Combination Composition of Aspirin

The present invention relates to a nanoparticulate composition comprising a combination of clopidogrel and aspirin, or salts or derivatives thereof. The composition comprises a combination of clopidogrel and aspirin, or a salt or derivative thereof, and preferably one or more surface stabilizers adsorbed on the surface of the drug. The combination of clopidogrel and aspirin, or salts thereof or derivatives thereof, has an effective average clopidogrel particle size of less than about 2000 nm.

Advantages of the combination formulation of nanoparticulate clopidogrel and aspirin of the present invention include, but are not limited to: (1) smaller tablet or other solid dosage form sizes; (2) smaller drug dosages required to achieve the same pharmacological effect as compared to conventional microcrystalline formulations of clopidogrel and aspirin; (3) increased bioavailability compared to conventional microcrystalline forms of clopidogrel; (4) improved pharmacokinetic profile; (5) increased dissolution rate of clopidogrel as compared to conventional microcrystalline formulations of the same clopidogrel; (6) Combination compositions of clopidogrel and aspirin can be used in combination with other active agents useful for the prevention and treatment of diseases caused by platelet aggregation; (7) reduction of gastrointestinal irritation due to enteric coated clopidogrel activators and / or aspirin.

The invention also relates to the combination of nanoparticulate clopidogrel and aspirin, or together, comprising one or more non-toxic and physiologically acceptable carriers, adjuvants, or vehicles, collectively referred to as carriers. Salts or derivatives thereof, compositions. The composition may be parenterally injected (eg, intravenous, intramuscular, or subcutaneous), oral administration of a solid, liquid, or aerosol formulation, vaginal, nasal, rectal, eye, local (powder, ointment, or drip) It may be formulated for drop, oral, intracratic, intraperitoneal, or topical administration, and equivalents thereof.

While certain pharmaceutically acceptable dosage forms can be used, preferred dosage forms of the invention are solid dosage forms. Representative solid dosage forms include, but are not limited to, tablets, capsules, sachets, lozenges, powders, pills, or granules, and solid dosage forms include, for example, fast melt dosage forms, Controlled release dosage forms, lyophilized dosage forms, delayed release dosage forms, extended release dosage forms, pulsatile release dosage forms, immediate release and Controlled release, mixed dosage forms, or combinations thereof. Solid dosage tablet formulations are preferred.

The invention has been described using several definitions, as set forth below and throughout the application.

As used herein, the term “effective average particle size of less than about 2000 nm” refers to, for example, sedimentation field flow fractionation, photon correlation spectroscopy, light scattering, disk centrifugation ( nanoparticulate form, as measured by weight, or by other suitable units of measurement (e.g., volume, number, etc.), as measured using disk centrifugation), and other methods known to those skilled in the art. It is meant that at least about 50% of the clopidogrel particles (or aspirin particles) have a size of less than about 2000 nm.

As used herein, an "about" will be understood by those skilled in the art, and changes may be made to some extent in the context when the "about" is used. Unless the context in which "about" is used is apparent to those skilled in the art, "about" will mean up to 10% or minus 10% of a particular value.

As used herein with reference to stable clopidogrel nanoparticulate particles, and stable aspirin nanoparticulate particles, “stable” includes, but is not limited to, one or more of the following parameters: (1) the particles due to interparticle attraction Does not aggregate or clump significantly or over time the particle size does not increase significantly; (2) does not change over time, as the physical structure of the particles is converted from an amorphous state to a crystalline state; (3) the particles are chemically stable; And / or (4) In the preparation of the nanoparticles of the present invention, clopidogrel or aspirin does not undergo a heating step at or above the melting point of clopidogrel or aspirin.

The term "conventional" or "non-nanoparticulate active agent" shall mean an active agent that is solubilized or has an effective average particle size of greater than about 2000 nm. Nanoparticulate active agents as defined herein have an effective average particle size of less than about 2000 nm.

The phrase “poorly water soluble drug” as used herein refers to a solubility of less than about 30 mg / ml, less than about 20 mg / ml, less than about 10 mg / ml, or less than about 1 mg / ml in water. It refers to a drug having.

When the phrase “therapeutically effective amount” is used herein, it refers to a drug dosage that provides a particular pharmacological response when the drug is administered to a significant number of subjects in need of treating the particular pharmacological response. Will mean. Although in certain instances a therapeutically effective amount of a drug administered to a particular subject is considered to be a therapeutically effective amount for those skilled in the art, it should be emphasized that this is not always effective when treating the diseases / diseases described herein. .

II . Nanoparticle type of the present invention Clopidogrel  Desirable features of the formulation of aspirin

A. Increased  Bioavailability

Compositions of the present invention comprising a combination of nanoparticulate clopidogrel and aspirin, or salts or derivatives thereof, exhibit increased bioavailability of clopidogrel and require lower dosages when compared to previous conventional clopidogrel formulations. Proposed. In one embodiment of the invention, according to standard pharmacokinetic practice, the nanoparticulate clopidogrel compositions are about 50% larger, about 40% larger, about 30% larger, about 20% larger than conventional dosage formulations. , Or about 10% greater bioavailability.

B. Improved Pharmacokinetics  profile

The combination of the nanoparticulate clopidogrel and aspirin of the present invention, or a salt or derivative thereof thereof, provides an improved drug wherein the maximum plasma concentration of clopidogrel at a given dose is higher than the maximum plasma concentration seen after administration of a conventional dosage form. It is proposed to represent a kinetic profile. In addition, the time to reach maximum plasma concentration will be shorter in nanoparticulate clopidogrel. This change will improve the therapeutic efficiency of clopidogrel.

The present invention preferably provides a composition comprising at least one nanoparticulate clopidogrel or derivative thereof or salt thereof, and optionally conventional microcrystalline or nanoparticulate aspirin, having a desirable pharmacokinetic profile when administered to a mammalian subject. to provide. Preferred pharmacokinetic profiles of the compositions of the present invention preferably include, but are not limited to: (1) the C _max of clopidogrel or its derivatives or salts thereof, as analyzed in the plasma of a mammalian subject after administration, is the same Preferably greater than the C _max of the non-nanoparticulate preparation of the same clopidogrel administered at a dose; And / or (2) the AUC of clopidogrel or its derivative or salt thereof analyzed in the plasma of the mammalian subject after administration is preferably greater than the AUC of the same non-nanoparticulate formulation of the same clopidogrel administered at the same dose; And / or (3) T _max of clopidogrel or a derivative thereof or salt thereof, analyzed in the plasma of a mammalian subject after administration, is preferably more than T _max of a non-nanoparticulate formulation of the same clopidogrel administered at the same dose. small.

In addition, the present invention includes nanoparticulate aspirin, and (1) a non-nanoparticulate form of aspirin administered with the same dose of C _max of aspirin or a salt thereof or derivative thereof analyzed in the plasma of a mammalian subject after administration Preferably greater than the C _{max of the} formulation; And / or (2) the AUC of the aspirin or salt thereof or derivative thereof analyzed in the plasma of the mammalian subject after administration is preferably greater than the AUC of the non-nanoparticulate formulation of aspirin administered at the same dose; And / or (3) the T _max of the aspirin or salt thereof or derivative thereof analyzed in the plasma of the mammalian subject after administration is preferably more than the T _max of the non-nanoparticulate formulation of the same aspirin administered at the same dose. Compositions that provide smallness.

For example, in one embodiment, a composition comprising nanoparticulate clopidogrel or a salt or derivative thereof, and one or more surface stabilizers is compared with a non-nanoparticulate formulation of the same clopidogrel administered at the same dose. In pharmacokinetic tests, up to about 90%, up to about 80%, up to about 70%, up to about 60%, up to about 50%, up to about 30%, up to about 25 of the T _max exhibited by the non-nanoparticulate clopidogrel formulation T _max is at most%, at most about 20%, at most about 15%, at most about 10%, or at most about 5%.

In another embodiment, a composition comprising a nanoparticulate clopidogrel or derivative thereof or a salt thereof, and one or more surface stabilizers is tested in a comparative pharmacokinetic test with a non-nanoparticulate formulation of the same clopidogrel administered at the same dose. At least about 50%, at least about 100%, at least about 200%, at least about 300%, at least about 400%, at least about 500%, at least about 600%, at least about C _{max as} represented by the non-nanoparticle clopidogrel At least about 800%, at least about 900%, at least about 1000%, at least about 1100%, at least about 1200%, at least about 1300%, at least about 1400%, at least about 1500%, at least about 1600%, about 1700 C _max greater than or equal to about 1800% or greater than or _equal to about 1900%.

In another embodiment, a composition comprising a nanoparticulate clopidogrel or derivative thereof or a salt thereof, and one or more surface stabilizers is compared with a non-nanoparticulate clopidogrel formulation of the same clopidogrel administered at the same dose. At least about 25%, at least about 50%, at least about 75%, at least about 100%, at least about 125%, at least about 150%, at least about 175%, at least about 200 than the AUC exhibited by non-nanoparticle clopidogrel At least about, at least about 225%, at least about 250%, at least about 275%, at least about 300%, at least about 350%, at least about 400%, at least about 450%, at least about 500%, at least about 550%, about 600 About 650% or more, about 700% or more, about 750% or more, about 800% or more, about 850% or more, about 900% or more, about 950% or more, about 1000% or more, about 1050% or more, about 1100 At least%, at least about 1150% or at least about 1200% greater AUC.

As used herein, the preferred pharmacokinetic profile is the pharmacokinetic profile measured after initial administration of clopidogrel or a derivative or salt thereof.

C. Of the Invention Clopidogrel Of aspirin composition Pharmacokinetics  Profile of the object ingesting the composition feeding  condition( fed state ) Or fasting state ( fasted  not affected by the state.

The present invention includes clopidogrel, and optionally nanoparticulate clopidogrel and aspirin, or derivatives or salts thereof, wherein the pharmacokinetic profile of aspirin is substantially unaffected by the fed or fasted state of the subject ingesting the composition. It comprises a composition to be. This means that when the nanoparticulate clopidogrel / aspirin composition is administered in the fasted state versus the fed state, there is no substantial difference in the amount of drug absorbed or the rate of drug absorption.

Benefits of dosage formulations that substantially eliminate the effects of food include increased convenience of the subject, thus increasing the compliance of the subject, because the subject may be able to identify whether they should administer the medicine with or without food. Because there is no need. This is important because, for subjects with poor compliance, an increase in the medical condition in which the drug is prescribed can be observed.

D. feeding  Of the present invention when administered in a state of fasting versus state Clopidogrel Bioequivalence of aspirin compositions bioequivalency )

The present invention also provides compositions comprising nanoparticulate clopidogrel and aspirin, or derivatives thereof or salts thereof, wherein the administration of the composition to the fasting subject is biologically equivalent to the administration of the composition to the fed subject.

When administered in a fasted state versus an fed state, the absorption (absorption of clopidogrel, aspirin, or a combination thereof) of the clopidogrel / aspirin compositions of the present invention is preferably less than about 100%, less than about 95%, less than about 90% Less than about 85%, less than about 80%, less than about 75%, less than about 70%, less than about 65%, less than about 60%, less than about 55%, less than about 50%, less than about 45%, less than about 40% , Less than about 35%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, or less than about 3%.

In one embodiment of the invention, the invention is particularly defined as defined in the guidelines of C _max and AUC provided by the U.S. Food and Drug Administration and the corresponding European regulatory agency (EMEA) (clopidogrel, aspirin or C _max and AUC), one or more nanoparticulate clopidogrel, wherein the administration of the composition to the fasting subject is biologically equivalent to the administration of the composition to the fed subject, and the aspirin may be of nanoparticulate size It includes a composition comprising a. According to the US FDA guidelines, two products or methods are biologically equivalent if the 90% Confidence Interval (CI) of AUC and C _max is between 0.80 and 1.25 (T _max measurements are not equivalent to biological equivalents for regulatory purposes). Not relevant). In order to show bioequivalence between two compounds or conditions of administration according to the European EMEA Directive, 90% CI of AUC must be 0.80 to 1.25 and 90% CI of C _max must be 0.70 to 1.43.

E. Of the Invention Clopidogrel and  Dissolution profile of combination of aspirin ( dissolution profile )

Compositions of the present invention comprising a combination of nanoparticulate clopidogrel and aspirin, or salts or derivatives thereof, are unexpectedly proposed to have dramatic dissolution profiles. Rapid dissolution of the administered active agent is preferred because faster dissolution generally leads to faster onset of action and greater bioavailability. In order to improve the dissolution profile and bioavailability of the combination of clopidogrel and aspirin, it would be useful to increase the dissolution of the drug to reach levels close to 100%.

The clopidogrel component of the present invention preferably has a dissolution profile in which at least about 20% of the composition dissolves within about 5 minutes. In another embodiment of the present invention, at least about 30% or at least about 40% of the clopidogrel composition dissolves within about 5 minutes. In yet another embodiment of the present invention, at least about 40%, at least about 50%, at least about 60%, at least about 70% or at least about 80% of the clopidogrel composition dissolves within about 10 minutes. Finally, in another embodiment of the present invention, preferably at least about 70%, at least about 80%, at least about 90%, or at least about 100% of the clopidogrel composition dissolves within about 20 minutes.

Preferably, dissolution is measured in a discriminating medium. Such a dissolution medium will create two very different dissolution curves for two products with very different dissolution profiles in gastric fluid, ie the dissolution medium is a precursor to in vivo dissolution of the composition. . An exemplary dissolution medium is an aqueous medium comprising the surfactant sodium lauryl sulfate at 0.025 M. The determination of the dissolved amount can be carried out by spectroscopy. Rotating blade method (European Pharmacopoeia) can be used to measure dissolution.

F. Of the Invention Clopidogrel  Redispersibility of Combination Compositions of Aspirin redispersibility )

Another feature of a composition comprising a combination of clopidogrel and aspirin, or salts or derivatives thereof, is that the composition has an effective average particle size of redispersed clopidogrel particles, aspirin particles, or a combination thereof of less than about 2 microns. To redistribute to This is important because, once administered, the clopidogrel and aspirin combination composition of the present invention will not substantially redisperse in nanoparticulate size, and the dosage form will lose the benefits gained by formulating the clopidogrel and aspirin formulation in nanoparticulate size. Because it can.

This is because nanoparticulate active agent compositions benefit from the small particle size of the active agent; If the active agent does not disperse to a small particle size after administration, the “clump” or agglomerated active particles due to the thermodynamic driving force to achieve an extremely high surface free energy and a total reduction in free energy of the nanoparticulate system. Is formed. With the generation of the aggregated particles, the bioavailability of the dosage form will drop below the bioavailability observed with the liquid dispersion formulation of the nanoparticulate active agent.

In addition, the nanoparticulate clopidogrel / aspirin compositions can be reconstituted in biorelevant aqueous media such that the effective average particle size of the redispersed clopidogrel particles, aspirin particles, or combinations thereof is less than about 2 microns. As evidenced by reconstitution / redispersion, after administration to a mammal or animal, such as a human, a dramatic redispersion of nanoparticulate clopidogrel particles, aspirin particles, or combinations thereof is shown. The biorelated aqueous medium can be any aqueous medium that exhibits the desired ionic strength and pH that forms the basis of the biorelevance of the medium. Preferred pH and ionic strength are representative of the physiological conditions found in the human body. The biorelevant aqueous medium can be, for example, an aqueous solution of an electrolyte exhibiting a desired pH and ionic strength or an aqueous solution of a predetermined salt, acid, or base, or a combination thereof.

Bio-related pH is well known in the art. For example, in the stomach, the pH ranges from slightly less than 2 (but typically greater than 1) to 4 or 5. In small intestines, the pH may range from 4 to 6, and in the colon, the pH may range from 6 to 8. Bio-related ionic strength is also well known in the art. Fasting gastric juice has an ionic strength of about 0.1M, while fasting serous has an ionic strength of about 0.14. For example, Lindahl et al . , "Characterization of Fluids from the Stomach and Proximal Jejunum in Men and Women," Pharm . Res . , 14 (4): 497-502 (1997).

It is believed that the pH and ionic strength of the test solution is more important than the content of certain chemicals. Thus, appropriate pH and ionic strength values are determined by strong acids, strong bases, salts, single or complex conjugate acid-base pairs (ie, weak acids and corresponding salts of those acids), monoprotic electrolytes and polyprotic. ) Can be obtained through numerous combinations of electrolytes and the like.

Representative electrolyte solutions can be, but are not limited to, HCl solutions in the range of about 0.001 to about 0.1 N concentration, and NaCl solutions in the range of about 0.001 to about 0.1 M concentration, and mixtures thereof. For example, the electrolyte solution may contain about 0.1 N or less HCl, about 0.01 N or less HCl, about 0.001 N or less HCl, about 0.1 M or less NaCl, about 0.01 M or less NaCl, about 0.001 M or less NaCl, and mixtures thereof, but is not limited to these. Of these electrolyte solutions, 0.01 M HCl and / or 0.1 M NaCl are most representative of fasting human physiological conditions because of the pH and ionic strength conditions of the adjacent gastrointestinal tract.

The electrolyte concentrations of 0.001 N HCl, 0.01 N HCl, and 0.1 N HCl correspond to pH 3, pH 2, and pH 1, respectively. Thus, 0.01 N HCl solution simulates the usual acidic conditions found in the stomach. Although concentrations higher than 0.1 M can be used to simulate feeding conditions in the human GI tract, 0.1 M NaCl solution is an approximation suitable for the ionic strength conditions found throughout the body, including gastrointestinal fluid. to provide.

Representative salts, acids, base solutions or combinations thereof that exhibit the desired pH and ionic strength include sodium, potassium and calcium salts of phosphoric acid / phosphate + chlorides, sodium, potassium and calcium salts of carbonic acid / acetate salts, carbonates / bicarbonates Sodium, potassium and calcium salts of salts + chlorides, and sodium, potassium and calcium salts of citric acid / citrate salts + chlorides, but are not limited to these.

In one embodiment of the present invention, the clopidogrel particles, aspirin particles, or combinations thereof that are redispersed (redispersed in water, in a biorelevant medium, or in any suitable liquid medium) are light-scattering methods, microscopes, or other When measured by a suitable method, less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, less than about 1600 nm, less than about 1500 nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm, about 1100 less than about nm, less than about 1000 nm, less than about 900 nm, less than about 800 nm, less than about 700 nm, less than about 600 nm, less than about 500 nm, less than about 400 nm, less than about 300 nm, less than about 250 nm, about 200 It has an effective average particle size of less than nm, less than about 150 nm, less than about 100 nm, less than about 75 nm or less than about 50 nm.

Redispersibility can be tested using any suitable method known in the art. See, for example, US Pat. No. 6,375,986 for "Solid Dosing Nanoparticulate Compositions Comprising a Synergistic Combination of Polymeric Surface Stabilizers with Dioctyl Sodium Sulfosuccinate."

G. Used in combination with other active agents Clopidogrel and  Combination Composition of Aspirin

Compositions comprising clopidogrel and aspirin, or salts or derivatives thereof, may further comprise one or more compounds useful for the prevention and treatment of diseases caused by platelet aggregation, or combination compositions of clopidogrel and aspirin may be such compounds It can be administered in combination with. Examples of the compound include, but are not limited to, calcium-entry blocking agents, antianginal agents, cardiac glycosides, vasodilators, antihypertensive agents, blood lipid-lowering agents, antiarrhythmic agents, And antithrombotic agents.

H. of the present invention Enteric  Coated Clopidogrel  And / or reduce gastrointestinal irritation of the combination composition of aspirin

An additional feature of the compositions of the present invention is that the compositions can advantageously be enteric or film coated to reduce gastrointestinal irritation (eg, irritation of the stomach and / or esophagus) in the patient. For example, in some embodiments, solid dosage forms comprising clopidogrel or salts or derivatives thereof may be enteric or film coated. In another embodiment, solid dosage forms comprising a combination of clopidogrel and aspirin, or salts or derivatives thereof, may be enteric or film coated.

The enteric coating enables the active agent (s) to be delivered to a particular location in the body, for example, to the duodenum, either the lower GI tract or the colon, or the upper part of the intestine or the small intestine.

For example, in some embodiments, about 0.05% or less, about 0.5% or less, about 0.5% or less of the active agent (eg, clopidogrel and / or aspirin) of the enteric coated composition of the present invention relative to the total dose administered to the subject Up to 1%, up to about 5%, up to about 10%, up to about 20%, up to about 30%, or up to about 40% dissolve in the stomach of the object. In another embodiment, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90% of the active agent (eg, clopidogrel and / or aspirin) relative to the total dose administered to the subject At least about 95%, at least about 97%, or at least about 100% is released from the intestines of the object.

Examples of suitable film-coating polymers include, for example, cellulose acetate phthalate, cellulose acetate trimaletate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, Eudragit® polyacrylic acid and polyacrylates. And enteric polymer coating materials such as methacrylate coatings, polyvinyl acetaldiethylamino acetate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate trimellitate, shellac; For example, carboxyvinyl polymer, sodium alginate, sodium carmellose, calcium carmelose, sodium carboxymethyl starch, polyvinyl alcohol, hydroxyethyl cellulose, methyl cellulose, gelatin, starch and cellulose-based crosslinking Bonded polymers, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, crosslinked starch, microcrystalline cellulose, chitin, cellulose acetate, cellulose propionate, cellulose acetate propionate , Cellulose acetate butyrate, cellulose triacetate, aminoacryl-methacrylate copolymer (Eudragit® RS-PM, Rohm & Haas), pullulan, collagen, casein agar, gum arabic, sodium carboxymethyl cellulose, carboxymethyl ethyl cellulose, Swellable Chin Polymeric, poly (hydroxyalkyl methacrylate) (molecular weight about 5 k-5,000 k), polyvinylpyrrolidone (molecular weight about 10 k-360 k), anionic and cationic hydrogels, lower acetate residues (low polyvinyl alcohol with acetate residual, expandable mixture of agar and carboxymethyl cellulose, copolymer of maleic anhydride and styrene, ethylene, propylene or isobutylene, pectin (molecular weight about 30 k-300 k), agar, acacia , Polysaccharides such as karaya, tragacanth, algin and guar, polyacrylamide, Polyox® polyethylene oxide (molecular weight about 100 k-5,000 k), AquaKeep® acrylate polymer, polyglucan Hydrogels and gel-forming such as diesters of crosslinked polyvinyl alcohol and poly N-vinyl-2-pyrrolidone, sodium starch glycolate (e.g., Explotab®; Edward Mandell C. Ltd.) (gel-forming) materials; Polysaccharides, methyl cellulose, sodium or calcium carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, nitrocellulose, carboxymethyl cellulose, cellulose ethers, poly (ethylene terphthalate), Poly (vinyl isobutyl ether), polyurethane, polyethylene oxide (e.g. Polyox®, Union Carbide), methyl ethyl cellulose, ethylhydroxy ethylcellulose, cellulose acetate, ethylcellulose, cellulose butyrate, cellulose propionate, Gelatin, collagen, starch, maltodextrin, pullulan, polyvinyl pyrrolidone, polyvinyl alcohol, polyvinyl acetate, glycerol fatty acid esters, polyacrylamides, polyacrylic acids, copolymers of methacrylic acid or methacrylic acid (e.g. For example, Eudragit ®, Rohm and Haas), other acrylic acid derivatives, ethyl acrylate-methyl methacrylate copolymer, sorbitan ester, polydimethyl siloxane, natural gum, lecithin, pectin, alginate, ammonia alginate, sodium Hydrophilic polymers such as calcium, potassium alginate, propylene glycol alginate, agar and gum; Arabian gum, karaya, locust bean, tragacanth, carrageenan, guar, xanthan, scleroglucan and mixtures thereof and combinations thereof.

III . Nano particle type Clopidogrel  Combination Composition of Aspirin

The present invention provides a composition comprising a combination of clopidogrel and aspirin, or a salt or derivative thereof, and at least one surface stabilizer. The surface stabilizer may be adsorbed or associated with the surface of clopidogrel particles, aspirin particles, or particles comprising clopidogrel and aspirin. Particularly useful surface stabilizers herein are preferably attached to or associated with the surface of the active agent, but do not chemically react with clopidogrel and aspirin particles or by themselves. Individually adsorbed molecules in the surface stabilizer are essentially free of intermolecular cross-links.

In addition, the present invention provides a composition comprising a combination of clopidogrel and aspirin, or a salt or derivative thereof, together with one or more non-toxic physiologically acceptable carriers, adjuvants, or vehicles, collectively referred to as carriers. Include. The composition may be used for parenteral injection (eg, intravenous, intramuscular, or subcutaneous), oral administration of a solid, liquid, or aerosol formulation, vagina, nose, rectum, eye, topical (powder, ointment or drop), oral cavity It may be formulated for intravitreal, intraperitoneal, or topical administration and equivalents thereof.

A. Active Particles

The composition of the present invention comprises nanoparticulate clopidogrel particles and aspirin, which may be in nanoparticulate size.

Clopidogrel particles may comprise salts or derivatives thereof, such as clopidogrel or clopidogrel bisulfate. Clopidogrel particles can be crystalline phase, semi-crystalline phase, amorphous phase, semi-amorphous phase, or a combination thereof.

Aspirin particles may comprise aspirin or salts thereof or derivatives thereof. Aspirin particles can be in crystalline phase, semi-crystalline phase, amorphous phase, semi-amorphous phase, or a combination thereof.

B. Surface Stabilizer

Combinations of one or more surface stabilizers can be used in the present invention. For example, if aspirin is present in nanoparticulate size, two different surface stabilizers can be used for nanoparticulate clopidogrel and nanoparticulate aspirin. Alternatively, although both clopidogrel and aspirin are present in nanoparticulate size, only one form of surface stabilizer can be used. Useful surface stabilizers that can be used in the present invention include, but are not limited to, known organic and inorganic pharmaceutical excipients. Such excipients include various polymers, low molecular weight oligomers, natural products, and surfactants. Surface stabilizers include nonionic, ionic, anionic, cationic, and zwitterionic surface stabilizers or compounds.

Representative examples of surface stabilizers include hydroxypropyl methylcellulose (now known as hypromellose), hydroxypropylcellulose, polyvinylpyrrolidone, sodium lauryl sulfate, dioctylsulfosuccinate, gelatin , Casein, lecithin (phosphatide), dextran, gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying Wax (cetomacrogol emulsifying wax), sorbitan esters, polyoxyethylene alkyl ethers (e.g. macrogol ethers such as Setomacrogol 1000), polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters (e.g. , (Tweens ^®) tween 20 ^® and tween 80 ^® (ICI Speciality Chemicals) commercially available, such as the Twin ); Polyethylene glycols (eg Carbowax 3550 ^® and 934 ^® (Union Carbide)), polyoxyethylene stearate, colloidal silicon dioxide, phosphate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose , 4- (1,1,3) comprising hydroxyethyl cellulose, hypromellose phthalate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol (PVA), ethylene oxide and formaldehyde , 3-tetramethylbutyl) -phenolic polymer (also known as tyloxapol, superione, and triton), poloxamer (e.g. Pluronic, a block copolymer of ethylene oxide and propylene oxide) F68 ^® and F108 ^® ); Pollock samin (e. G., Also, known as Poloxamine ^® 908, ethylenediaminetetraacetate on propylene oxide and ethylene tetrafunctional shelf (tetrafunctional) block copolymer is Tetronic 908 ^® is derived from a continuous addition of the oxide (BASF Wyandotte Corporation , Parsippany, NJ)); Tetronic 1508 ^® (T-1508) from BASF Wyandotte Corporation, Triton ^® X-200 (Rohm and Haas), an alkyl aryl polyether sulfonate; Crodestas F-110 ^® (Croda Inc.), a mixture of sucrose stearate and sucrose distearate; P-isononylphenoxypoly- (glycidol), also known as Olin ^® -1OG or Surfactant 10-G ^® (Olin Chemicals, Stamford, CT); And Crodestas SL-40 ^® (Croda, Inc.); And SA9OHCO (Eastman Kodak Co.) with C ₁₈ H ₃₇ CH ₂ (CON (CH ₃ ) —CH ₂ (CHOH) ₄ (CH ₂ 0H) ₂ ; decanoyl-N-methylglucamide; n-decyl β- D-glucopyranoside; n-decyl β-D-maltopyranoside; n-dodecyl β-D-glucopyranoside; n-dodecyl β-D-maltoside; heptanoyl-N-methylglycol Lucamide, n-heptyl-β-D-glucopyranoside, n-heptyl β-D-thioglucoside, n-hexyl β-D-glucopyranoside, nonanoyl-N-methylglucamide; n-noyl β-D-glucopyranoside; octanoyl-N-methylglucamide; n-octyl-β-D-glucopyranoside; octyl β-D-thioglucopyranoside; PEG-phosphori Feed, PEG-cholesterol, PEG-cholesterol derivatives, PEG-vitamin A, PEG-vitamin E, lysozyme, random copolymers of vinyl pyrrolidone and vinyl acetate, and equivalents thereof.

Examples of useful cationic surface stabilizers include polymers, biopolymers, polysaccharides, cellulosic, alginates, phospholipids, and zwitterionic stabilizers, poly-n-methylpyridinium, anthriol ( anthryul) pyridinium chloride, cationic phospholipid, chitosan, polylysine, polyvinylimidazole, polybrene, polymethylmethacrylate trimethylammonium bromide bromide (PMMTMABr), hexyldecyltrimethylammonium bromide (HDMAB) And nonpolymeric compounds such as, but not limited to, polyvinylpyrrolidone-2-dimethylaminoethyl methacrylate dimethyl sulfate.

Other useful cationic stabilizers include cationic lipids, sulfonium, phosphonium, and stearyltrimethylammonium chloride, benzyl-di (2-chloroethyl) ethylammonium bromide, coconut trimethyl ammonium chloride or bromide, coconut methyl dihydroxyethyl ammonium chloride or bromide, decyl triethyl ammonium chloride, decyl dimethyl hydroxyethyl ammonium chloride or bromide, C _{12 - 15} dimethyl hydroxyethyl ammonium chloride or bromide, coconut dimethyl hydroxyethyl ammonium chloride or bromide, myristyl trimethyl ammonium methyl alcohol sulphate, lauryl dimethyl benzyl ammonium chloride or bromide, La (not tenok a) lauryl dimethyl _quaternary ammonium chloride or bromide, N- alkyl (C _{12 -18)} dimethyl benzyl ammonium chloride, N- alkyl (C _14-18) dimethyl - Be chloride, N- tetradecyl dimethyl benzyl ammonium chloride monohydrate, dimethyl didecyl ammonium chloride, N- alkyl and (C _{12 -14)} dimethyl 1-naphthylmethyl ammonium chloride, trimethylammonium halide, alkyl-trimethyl ammonium salt And dialkyl-dimethylammonium salts, lauryl trimethyl ammonium chloride, ethoxylated alkylamidoalkyldialkylammonium salts and / or ethoxylated trialkyl ammonium salts, dialkylbenzene dialkylammonium chlorides, N - didecyl dimethyl ammonium chloride, N- tetradecyl dimethyl benzyl ammonium chloride monohydrate, N- alkyl (C _{12 -14)} dimethyl 1-naphthylmethyl ammonium chloride and dodecyl dimethyl benzyl ammonium chloride, dialkyl benzene alkyl ammonium chloride, Lauryl trimethyl ammonium chloride, alkylbenzyl methyl ammonium chloride, al Kyl benzyl dimethyl ammonium bromide, C ₁₂ , C ₁₅ , C ₁₇ trimethyl ammonium bromide, dodecylbenzyl triethyl ammonium chloride, poly-diallyldimethylammonium chloride (DADMAC), dimethyl ammonium chloride, alkyldimethylammonium halogenide, tricetyl Methyl ammonium chloride, decyltrimethylammonium bromide, dodecyltriethylammonium bromide, tetradecyltrimethylammonium bromide, methyl trioctylammonium chloride (ALIQUAT 336 ^TM ), polyquat 10 (POLYQUAT 10 ^TM ), tetrabutylammonium bromide, benzyl trimethylammonium Bromide, choline esters (choline esters such as choline esters of fatty acids), benzalkonium chloride, stearalkonium chloride compounds (compounds such as stearyltrimonium chloride and distearyldimonium chloride), cetyl Bipyridinium bromide or chloride, quaternized (quaternized) polyoxyethylated halide salt, Mira pole (MIRAPOL ^TM) and alkaline quart ^{(ALKAQUAT TM) (Alkaril Chemical Company} ), 4 quaternary ammonium compounds, such as alkylpyridinium salts of alkyl amines ; Amines such as alkylamines, dialkylamines, alkanolamines, polyethylenepolyamines, N, N-dialkylaminoalkyl acrylates, and vinyl pyridine; Amine salts and amine oxides such as lauryl amine acetate, stearyl amine acetate, alkylpyridinium salts, and alkylimidazolysone salts; Imide azolinium salts; Protonated quaternary acrylamides; Methylated quaternary polymers such as poly [diallyl dimethylammonium chloride] and poly- [N-methyl vinyl pyridinium chloride]; And cationic guar, but is not limited to these.

Such representative cationic surface stabilizers and other useful cationic surface stabilizers are described in J. Cross and E. Singer, Cationic Surfactants: Analytical and Biological Evaluation (Marcel Dekker, 1994); P. and D. Rubingh (editor), Cationic Surfactants: Physical Chemistry (Marcel Dekker, 1991); And J. Richmond, Cationic Surfactants: Organic Chemistry (Marcel Dekker, 1990).

Nonpolymeric surface stabilizers include benzalkonium chloride, carbonium compounds, phosphonium compounds, oxonium compounds, halonium compounds, cationic organometallic compounds, quaternary phosphorus compounds, pyridinium compounds, anilinium compounds, ammonium compounds Certain nonpolymeric compounds such as hydroxyammonium compounds, primary ammonium compounds, secondary ammonium compounds, tertiary ammonium compounds, and quaternary ammonium compounds such as the formula NR ₁ R ₂ R ₃ R ₄ ⁽⁺⁾ . For compounds of formula NR ₁ R ₂ R ₃ R ₄ ⁽⁺⁾ ,

(i) none of R ₁ -R ₄ are CH ₃ ;

(ii) one of R ₁ -R ₄ is CH ₃ ;

(iii) three of R ₁ -R ₄ are CH ₃ ;

(iv) all of R ₁ -R ₄ are CH ₃ ;

(v) two of R ₁ -R ₄ are CH ₃ , one of R ₁ -R ₄ is C ₆ H ₅ CH ₂ , and one of R ₁ -R ₄ has 7 or less carbon atoms An alkyl chain;

(vi) alkyl of two of R ₁ -R ₄ is CH ₃ , one of R ₁ -R ₄ is C ₆ H ₅ CH ₂ , and one of R ₁ -R ₄ has 19 or more carbon atoms A chain;

(vii) two of R ₁ -R ₄ are CH ₃ and _one of R ₁ -R ₄ is a C ₆ H ₅ (CH ₂ ) _n group where n>1;

(viii) two of R ₁ -R ₄ are CH ₃ , one of R ₁ -R ₄ is C ₆ H ₅ CH ₂ , and one of R ₁ -R ₄ comprises one or more heteroatoms;

(ix) two of R ₁ -R ₄ are CH ₃ , one of R ₁ -R ₄ is C ₆ H ₅ CH ₂ , and one of R ₁ -R ₄ comprises at least one halogen;

(x) two of R ₁ -R ₄ are CH ₃ , one of R ₁ -R ₄ is C ₆ H ₅ CH ₂ , and one of R ₁ -R ₄ is one or more cyclic fragments It includes;

(xi) two of R ₁ -R ₄ are CH ₃ and one of R ₁ -R ₄ is a phenyl ring; or

(xii) two of R ₁ -R ₄ are CH ₃ and two of R ₁ -R ₄ are purely aliphatic fragments.

Such compounds include behenalkonium chloride, benzethonium chloride, cetylpyridinium chloride, behentrimonium chloride, lauralkonium chloride, cetalkonium chloride, Cetrimonium bromide, cetrimonium chloride, cetylamine hydrofluoride, chlorallylmethenamine chloride (Quaternium-15), distearyldimonium chloride (Quaternium-5) Dodecyl dimethyl ethylbenzyl ammonium chloride (Quaternium-14), quaternium-22, quaternium-26, quaternium-18 hectorite ), Dimethylaminoethylchloride hydrochloride, cysteine hydrochloride, diethanolammonium POE (10) oletyl ether phosphate, diethanolam POE (3) oleyl ether phosphate, tallow alkonium chloride, dimethyl dioctadecylammonium bentonite, stearalkonium chloride, domiphen bromide, denatonium benzoate, Myristalkonium chloride, laurtrimonium chloride, ethylenediamine dihydrochloride, guanidine hydrochloride, pyridoxine HCl, ifopetamine hydrochloride, meglumine hydrochloride, methylbenzethonium chloride , Myritrimonium bromide, oleyltrimonium chloride, polyquaternium-1, procaine hydrochloride, cocobetaine, stearalkonium bentonite, stearalconium hectorite, stearyl Trihydroxyethyl propylenediamine dihydrofluoria Such as, but not limited to, resinous trimonium chloride, and hexadecyltrimethyl ammonium bromide.

Surface stabilizers are commercially available and / or can be prepared by methods known in the art. Most of these surface stabilizers are known pharmaceutical excipients, Handbook of Pharmaceutical Excipients (The Pharmaceutical Press), published jointly by the American Pharmaceutical Association and The Pharmaceutical Society of Great Britain. , 2000), which is specifically incorporated herein by reference.

C. Other Pharmaceutical Excipients

In addition, the pharmaceutical compositions of the present invention may include one or more binders, fillers, lubricants, suspending agents, sweetening agents, flavoring agents, preservatives, buffers, humectants, disintegrants, effervescent agents, and other excipients. Such excipients are well known in the art.

Examples of fillers are lactose monohydrate, lactose anhydrous and various starches; Examples of the binders include various cellulose and cross-coupling a polyvinylpyrrolidone, microcrystalline cellulose, microcrystalline cellulose, and silicified microcrystalline cellulose such as Avicel ^® the PH1O1 and ^{Avicel ® PH102 (ProSolv SMCC TM)} .

, A suitable lubricant, including agents that act on the fluidity (flowability) of the powder to be pressed has a colloidal silicon dioxide, talc, stearic acid, magnesium stearate, calcium stearate, such as Aerosil ^® 200, and silica gel.

Examples of sweeteners include certain natural or artificial sweeteners such as sucrose, xylitol, sodium saccharin, cyclamate, aspartame and assulfame. Examples of flavoring agents are Magnasweet ^® (trade name of MAFCO), bubble gum flavorings, and fruit flavoring flavorings, and equivalents thereof.

Examples of preservatives include potassium sorbate, methylparaben, propylparaben, benzoic acid and salts thereof, other esters of parahydroxybenzoic acid such as butylparaben, alcohols such as ethyl alcohol or benzyl alcohol, phenolic compounds such as phenol, And quaternary compounds such as benzalkonium chloride.

Suitable diluents include pharmaceutically acceptable inert fillers, such as microcrystalline cellulose, lactose, dibasic calcium phosphate, saccharides, and / or mixtures of those described above. Examples of diluents include microcrystalline celluloses such as Avicel ^® PH101 and Avicel ^® PH102; Lactose monohydrate, lactose such as anhydrous lactose, and Pharmatose ^® DCL21; 2, such as Emcompress ^® basic calcium phosphate; Mannitol; Starch; Sorbitol; Sucrose; And glucose.

Suitable disintegrants include polyvinyl pyrrolidone, corn starch, potato starch, maize starch, and modified starch, croscarmellose sodium, cross-povidone, sodium star slightly crosslinked. Chi glycolate, and mixtures thereof.

Examples of blowing agents are organic acids and pairs of foaming agents, such as carbonates or bicarbonates. Suitable organic acids include, for example, citric acid, tartaric acid, malic acid, fumaric acid, adipic acid, succinic acid, and alginic acid, and their anhydrides and acid salts thereof. Suitable carbonates and bicarbonates include, for example, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, magnesium carbonate, sodium glycine carbonate, L-lysine carbonate and arginine carbonate. Alternatively, only one sodium bicarbonate component may be present in the effervescent pair.

D. Nanoparticle Type Clopidogrel  Aspirin Blended Particle Size

The compositions of the present invention are less than about 2000 nm (ie, 2 microns), less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, about 1600 as measured by light-scattering methods, microscopy, or other suitable methods. less than about nm, less than about 1500 nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm, less than about 1100 nm, less than about 1000 nm, less than about 900 nm, less than about 800 nm, less than about 700 nm, about 600 Effective less than about nm, less than about 500 nm, less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about 200 nm, less than about 150 nm, less than about 100 nm, less than about 75 nm, or less than about 50 nm Nanoparticulate particles of clopidogrel, or salts or derivatives thereof, having an average particle size.

Optionally, the compositions of the present invention may be less than about 2000 nm (ie, 2 microns), less than about 1900 nm, less than about 1800 nm, about 1700 nm, as measured by light-scattering methods, microscopy, or other suitable methods. Less than about 1600 nm, less than about 1500 nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm, less than about 1100 nm, less than about 1000 nm, less than about 900 nm, less than about 800 nm, about 700 nm Less than about 600 nm, less than about 500 nm, less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about 200 nm, less than about 150 nm, less than about 100 nm, less than about 75 nm, or about 50 nanoparticulate particles of aspirin, or salts or derivatives thereof, having an effective average particle size of less than nm.

"Effective average particle size less than about 2000 nm" refers to clopidogrel, or 50% by weight (or volume, number, etc.) of the combination of clopidogrel and aspirin, including nanoparticulate aspirin, as measured by the above-known methods. By an appropriate measurement method) means a particle size below the effective average, ie, less than about 2000 nm, less than about 1900 nm, less than about 1800 nm. In another embodiment of the present invention, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95% or at least about 99% of the clopidogrel particles, aspirin particles, or combinations thereof are effective. Particle sizes below average, ie, less than about 2000 nm, less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, and the like.

In the present invention, the D50 value of the nanoparticulate clopidogrel composition, the nanoparticulate aspirin composition, or a combination thereof is 50% (or by other suitable method such as volume, number, etc.) of the clopidogrel particles and / or aspirin particles. The corresponding particle size. Likewise, D90 is the particle size for which 90% by weight (by volume, number, etc.) of clopidogrel particles and / or aspirin particles is determined by other suitable measurement methods.

E. Clopidogrel  Aspirin Formulation and Concentrations of Surface Stabilizers

The combination of clopidogrel and aspirin, or salts or derivatives thereof, and the relative amounts of one or more surface stabilizers can vary widely. The optimal content of the individual components may depend, for example, on the combination of the particular clopidogrel and aspirin chosen, hydrophilic lipophilic balance (HLB), melting point, and surface tension of the surface stabilizer aqueous solution.

In a first embodiment of the present invention, the concentration of the combination of clopidogrel and aspirin is about 99.5 for the total combined dry weight of clopidogrel and aspirin and at least one surface stabilizer, which does not include other excipients. Weight percent to about 0.001 weight percent, about 95 weight percent to about 0.1 weight percent, or about 90 weight percent to about 0.5 weight percent. The concentration of at least one surface stabilizer is from about 0.5% to about 99.999% by weight, from about 5.0% to about 99.9% by weight of the combination of clopidogrel and aspirin and the total dry weight of the at least one surface stabilizer, which does not include other excipients. Weight percent, or from about 10 weight percent to about 99.5 weight percent.

In a second embodiment of the invention, the concentration of clopidogrel is from about 99.5 wt% to about 0.001 wt%, from about 95 wt% to about 0.1 with respect to the dry weight of clopidogrel and at least one surface stabilizer, comprising no other excipients. Weight percent, or from about 90 weight percent to about 0.5 weight percent. The concentration of at least one surface stabilizer is from about 0.5% to about 99.999% by weight, from about 5.0% to about 99.9% by weight, relative to the total dry weight of clopidogrel and at least one surface stabilizer, which does not include other excipients, or From about 10% to about 99.5% by weight.

In a third embodiment of the invention, the concentration of aspirin is from about 99.5 wt% to about 0.001 wt%, from about 95 wt% to about 0.1 with respect to the dry weight of the aspirin and at least one surface stabilizer, comprising no other excipients Weight percent, or from about 90 weight percent to about 0.5 weight percent. The concentration of at least one surface stabilizer is from about 0.5% to about 99.999%, from about 5.0% to about 99.9% by weight, relative to the total dry weight of aspirin and at least one surface stabilizer, which does not include other excipients, or From about 10% to about 99.5% by weight.

F. Representative Nanoparticle Type Clopidogrel With bisulfate  Formulation tablet formulation of aspirin

Several representative clopidogrel bisulfates and aspirin combined tablet formulations are provided below. Such representative formulations are intended to provide representative tablet formulations of the combination of clopidogrel bisulfate and aspirin that may be used in the methods of the invention, and are not intended to limit the claims in any respect. The representative tablet may also include a coating.

Typical Nanoparticulate Clopidogrel Bisulfate and Aspirin Combination Tablet Formulation ＃ 1 ingredient g / Kg Clopidogrel bisulfate and aspirin About 50 to about 500, each Hypromellose, USP About 10 to about 70 Docusate Sodium, USP About 1 to about 10 Sucrose, NF About 100 to about 500 Sodium Lauryl Sulfate, NF About 1 to about 40 Lactose Monohydrate, NF About 50 to about 400 Silicified microcrystalline cellulose About 50 to about 300 Crospovidone, NF About 20 to about 300 Magnesium Stearate, NF About 0.5 to about 5

Representative Nanoparticulate Clopidogrel Bisulfate and Aspirin Combination Tablet Formulation ＃ 2 ingredient g / Kg Clopidogrel bisulfate and aspirin About 100 to about 300, each Hypromellose, USP About 30 to about 50 Docusate Sodium, USP About 0.5 to about 10 Sucrose, NF About 100 to about 300 Sodium Lauryl Sulfate, NF About 1 to about 30 Lactose Monohydrate, NF About 100 to about 300 Silicified microcrystalline cellulose About 50 to about 200 Crospovidone, NF About 50 to about 200 Magnesium Stearate, NF About 0.5 to about 5

Representative Nanoparticulate Clopidogrel Bisulfate and Aspirin Combination Tablet Formulation ＃ 3 ingredient g / Kg Clopidogrel bisulfate and aspirin About 200 to about 225, each Hypromellose, USP About 42 to about 46 Docusate Sodium, USP About 2 to about 6 Sucrose, NF About 200 to about 225 Sodium Lauryl Sulfate, NF About 12 to about 18 Lactose Monohydrate, NF About 200 to about 205 Silicified microcrystalline cellulose About 130 to about 135 Crospovidone, NF About 112 to about 118 Magnesium Stearate, NF About 0.5 to about 3

Typical Nanoparticulate Clopidogrel Bisulfate and Aspirin Combination Tablet Formulation ＃ 4 ingredient g / Kg Clopidogrel bisulfate and aspirin About 119 to about 224, each Hypromellose, USP About 42 to about 46 Docusate Sodium, USP About 2 to about 6 Sucrose, NF About 119 to about 224 Sodium Lauryl Sulfate, NF About 12 to about 18 Lactose Monohydrate, NF About 119 to about 224 Silicified microcrystalline cellulose About 129 to about 134 Crospovidone, NF About 112 to about 118 Magnesium Stearate, NF About 0.5 to about 3

IV . Nano particle type Clopidogrel  Method for preparing a combination composition of aspirin

Compositions comprising a combination of nanoparticulate clopidogrel and aspirin, salts or derivatives thereof, may be prepared using, for example, milling, homogenization, precipitation, freezing, or template emulsion emulsion methods. Can be. Representative methods for preparing nanoparticulate compositions are described in the '684 patent. In addition, methods for preparing nanoparticulate compositions include US Pat. No. 5,518,187 for "Method of Grinding Pharmaceutical Substances;" US Patent No. 5,718,388 for "Continuous Method of Grinding Pharmaceutical Substances"; US Patent No. 5,862,999 for "Method of Grinding Pharmaceutical Substances"; US Patent No. 5,665,331 for "co-microprecipitation of nanoparticulate pharmaceutical drugs by crystal growth modifiers;" US Patent No. 5,662,883 for "Co-Microprecipitation of Nanoparticulate Pharmaceutical Drugs by Crystal Growth Modifiers; US Patent No. 5,560,932 for "Microprecipitation of Nanoparticulate Pharmaceutical Drugs"; US Patent No. 5,543,133 for "Method for Preparing X-Ray Contrast Compositions Comprising Nanoparticles"; US Patent No. 5,534,270 for "Method for Preparing Stable Drug Nanoparticles"; US Patent No. 5,510,118 for "Method for Preparing a Therapeutic Composition Including Nanoparticles"; And US Pat. No. 5,470,583 for "Methods for Producing Nanoparticulate Compositions Containing Charged Phospholipids for Reduced Density," all of which are specifically incorporated by reference. .

The resulting combination or dispersion of nanoparticulate clopidogrel and aspirin may be a liquid dispersion, gel, aerosol, ointment, cream, controlled release formulation, quick dissolving formulation, lyophilized formulation, tablet, capsule, delayed release formulation, It can be used as a solid or liquid dosage formulation, such as extended release formulations, pulsatile release formulations, mixed formulations of immediate release and controlled release.

Aspirin may be reduced in size at the same time as clopidogrel, or aspirin may be individually reduced in particle size (using the same or other methods) and then the nanoparticulate aspirin composition may be combined with the nanoparticulate clopidogrel formulation to According to the present invention. Alternatively, conventional microcrystalline aspirin can be added to the nanoparticulate clopidogrel to form a composition according to the present invention.

A. Nanoparticle Type Clopidogrel  To obtain a dispersion of the formulation of aspirin milling

Obtaining a nanoparticulate dispersion by milling clopidogrel, and optionally aspirin, or a salt thereof or derivative thereof, comprises dispersing clopidogrel particles in a liquid dispersion medium in which clopidogrel is poorly soluble, followed by grinding media. Applying mechanical means in the presence of to reduce the particle size of clopidogrel to a target effective mean particle size. The dispersion medium can be, for example, water, safflower seed oil, ethanol, t-butanol, glycerin, polyethylene glycol (PEG), hexane, or glycol. Preferred dispersion medium is water.

Clopidogrel particles may be reduced in size in the presence of one or more surface stabilizers. Alternatively, the clopidogrel particles may be contacted with one or more surface stabilizers after wear. Other compounds, such as diluents, may be added to the combination / surface stabilizer composition of clopidogrel and aspirin during the size reduction process. Dispersions can be prepared continuously or in batch mode.

B. Nanoparticle Type Clopidogrel  Precipitation to Obtain a Combination Composition of Aspirin

Another method of producing the desired nanoparticulate clopidogrel, and optionally aspirin, or salts or derivatives thereof, is by microprecipitation. This is a method for preparing a stable dispersion of poorly soluble activator in the presence of at least one surface stabilizer and at least one colloidal stability increasing surface active agent free of trace toxic solvents or solubilized heavy metal impurities. The method comprises, for example, (1) dissolving the combination of clopidogrel and aspirin in a suitable solvent; (2) adding the agent from step (1) to a solution comprising at least one surface stabilizer; And (3) precipitating the formulation from step (2) using an appropriate non-solvent. The method can then remove the salt produced by dialysis or diafiltration and concentration of the dispersion by conventional methods, if present.

C. Nanoparticle Type Clopidogrel  To obtain a combination composition of aspirin Homogenization

Representative homogenization methods for preparing nanoparticulate active agent compositions are described in US Pat. No. 5,510,118 for "Methods for Preparing Therapeutic Compositions Including Nanoparticles." The method comprises dispersing clopidogrel, and optionally aspirin, or a salt thereof or derivative thereof, in a liquid dispersion medium, and homogenizing the resulting dispersion to reduce the clopidogrel's particle size to the desired effective mean particle size. . Clopidogrel particles may be reduced in size in the presence of one or more surface stabilizers. Alternatively, the clopidogrel particles may be contacted with one or more surface stabilizers before or after abrasion. Other compounds, such as diluents, may be added to the clopidogrel / surface stabilizer composition before, during, or after the size reduction process. Dispersions can be prepared continuously or batchwise.

D. Nanoparticle Type Clopidogrel  Cryogenic method to obtain a combination composition of aspirin cryogenic methodology )

Another method of producing the desired nanoparticulate clopidogrel, and optionally aspirin, or salts or derivatives thereof, is by spray freezing into liquid (SFL). This method includes an organic solution or an organicoaqueous solution of clopidogrel with stabilizers, which is injected into cryogenic liquids such as liquid nitrogen. Droplets of the combined solution of clopidogrel and aspirin are frozen at a rate sufficient to minimize crystallization and particle growth, thus formulating nanostructured clopidogrel particles. Depending on the choice of solvent system and process conditions, the nanoparticulate clopidogrel particles can have various particle forms. In the separation step, the nitrogen and the solvent are removed under conditions that avoid agglomeration or ripening of clopidogrel particles.

As a complementary method of SFL, ultra rapid freezing (URF) can be used to make a combination of equivalent nanostructured clopidogrel and aspirin with a significantly increased surface area. URF includes organic or organic aqueous solutions of clopidogrel with stabilizers on cryogenic substrates.

E. Nanoparticle Type Clopidogrel  To obtain a combination composition of aspirin emulsion  Way

Another method of producing the desired nanoparticulate clopidogrel, and optionally aspirin, or salts or derivatives thereof, is by template emulsion. Template emulsions produce nanostructured clopidogrel particles with controlled particle size distribution and fast dissolution performance. The method includes preparing an oil-in-water emulsion and then swelling into a non-aqueous solution comprising clopidogrel and a stabilizer. The particle size distribution of clopidogrel particles is a direct result of the size of the emulsion droplets prior to loading clopidogrel, in which the characteristics can be controlled and optimized. In addition, through the selected use of solvents and stabilizers, emulsion stability is achieved without Ostwald ripening or with inhibition of Ostwald ripening. Subsequently, the solvent and water are removed and the clopidogrel particles with stabilized nanostructures are recovered. Various clopidogrel particle forms can be achieved through appropriate control of process conditions.

IV . Nano particle type Clopidogrel  Controlled Release of Combination Formulations of Aspirin

Another embodiment of the present invention comprises covering, in the polymeric coating or matrix, the combination particles of the nanoparticulate clopidogrel and aspirin described above. Since the solubility of the combination of clopidogrel and aspirin is pH-dependent, the rate of dissolution of the drug and the resulting bioavailability of the drug may change as the drug passes through different parts of the gastroenterologic system. Coating the particles for sustained and / or controlled release will result in an improved, consistent dissolution rate of the drug, thus avoiding concentration of the drug at high concentrations. Either or both of clopidogrel and aspirin may be coated.

Any coating material can be used that alters the release of the combined particles of nanoparticulate clopidogrel and aspirin in a targeted manner. In particular, suitable coating materials for use in the practice of the present invention include, but are not limited to, cellulose acetate phthalate, cellulose acetate trimaleate, hydroxy propyl methylcellulose phthalate, polyvinyl acetate phthalate, trade names Eudragit® RS and RL. Ammonio methacrylate copolymers such as polyacrylic acid and polyacrylates and methacrylate copolymers such as those sold under the trade names Eudragite S and L, polyvinyl acetaldiethylamino acetate, hydroxypropyl methylcellulose acetate succinate Polymer coating materials such as nates, shellacs; Carboxyvinyl polymer, sodium alginate, sodium carmellose, calcium carmellose, sodium carboxymethyl starch, polyvinyl alcohol, hydroxyethyl cellulose, methyl cellulose, gelatin, starch, and promoting water absorption and expansion of the polymer matrix Cellulose based crosslinked polymers with low degree of crosslinking, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, crosslinked starch, microcrystalline cellulose, chitin, aminoacryl-methacrylate co Polymers (Eudragit® RS-PM, Rohm & Haas), pullulan, collagen, casein, agar, gum arabic, sodium carboxymethyl cellulose, (expandable hydrophilic polymer) poly (hydroxyalkyl methacrylate) (molecular weight about 5 k -5,000 k), polyvinylpyrrolidone (molecular weight about 10 k-360 k), anionic and cationic hydrogels, lower sub Polyvinyl alcohol with tate residues, expandable mixtures of agar and carboxymethyl cellulose, copolymers of maleic anhydride and styrene, ethylene, propylene or isobutylene, pectin (molecular weight about 30 k-300 k), agar, acacia, Polysaccharides such as karaya, tragacanth, algin and guar, polyacrylamide, Polyox® polyethylene oxide (molecular weight about 100 k-5,000 k), AquaKeep® acrylate polymer, diester of polyglucan, crosslinked Hydrogels and gel-forming materials such as polyvinyl alcohol and poly N-vinyl-2-pyrrolidone, sodium starch glucolate (eg Explotab®; Edward Mandell C. Ltd.); Polysaccharides, methyl cellulose, sodium or calcium carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, nitro cellulose, carboxymethyl cellulose, cellulose ethers, polyethylene oxides (e.g., Polyox® , Union Carbide), methyl ethyl cellulose, ethyl hydroxy ethyl cellulose, cellulose acetate, cellulose butyrate, cellulose propionate, gelatin, collagen, starch, maltodextrin, pullulan, polyvinyl pyrrolidone, polyvinyl alcohol, poly Vinyl acetate, glycerol fatty acid esters, polyacrylamides, polyacrylic acids, copolymers of methacrylic acid or methacrylic acid (e.g. Eudragit®, Rohm and Haas), other acrylic acid derivatives, sorbitan esters, natural gums, lecithin , Pectin, alginate, cancer Nia alginate, sodium, calcium, potassium alginate, propylene glycol alginate, agar, and Arabian, Karaya, locust beans, tragacanth, carrageen, guar, xanthan, screloglucan and mixtures thereof and Hydrophilic polymers such as gums such as combinations thereof. As will be appreciated by those skilled in the art, excipients such as plasticisers, lubricants, solvents and the like may be added to the coating. Suitable plasticizers include, for example, acetylated monoglycerides; Butyl phthalyl butyl glycolate; Dibutyl tartrate; Diethyl phthalate acetate trimerate, hydroxy propyl methylcellulose phthalate, polyvinyl acetate phthalate, dimethyl phthalate; Ethyl phthalyl ethyl glycolate; glycerin; Propylene glycol; Triacetin; Citrate; Tripropioin; Diacetin; Dibutyl phthalate; Acetyl monoglycerides; Polyethylene glycol; Castor oil; Triethyl citrate; Polyhydric alcohol, glycerol, acetate ester, glycerol triacetate, acetyl triethyl citrate, dibenzyl phthalate, dihexyl phthalate, butyl octyl phthalate, diisononyl phthalate, butyl octyl phthalate, dioctyl azelate , Epoxidized tallate, triisooctyl trimellitate, diethylhexyl phthalate, di-n-octyl phthalate, di-i-octyl phthalate, di-i-decyl phthalate, di -n-undecyl phthalate, di-n-tridecyl phthalate, tri-2-ethylhexyl trimerate, di-2-ethylhexyl adipate, di-2-ethylhexyl sebacate, di 2-ethylhexyl azelate, dibutyl sebacate and mixtures thereof.

When the modified release component comprises a modified release matrix material, any suitable modified release matrix material or appropriate combination of modified release matrix materials may be used. Such materials are known to those skilled in the art. When the term "modified release matrix material" is used herein, it is used in vitro) or in vivo (in hydrophilic polymers, hydrophobic polymers and mixtures thereof that can modify the release of the active agent dispersed in vivo ). Modified release matrix materials suitable for the practice of this invention include, but are not limited to, hydroxyalkylcelluloses such as microcrystalline cellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose and hydroxypropylcellulose, polyethylene oxide, methylcellulose And alkyl celluloses such as ethyl cellulose, polyethylene glycol, polyvinylpyrrolidone, cellulose acetate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose acetate trimerate, polyvinylacetate phthalate, polyalkyl methacrylate, polyvinyl acetate and these It contains a mixture of.

V. Nanoparticulates of the Invention Clopidogrel  How to Use Combination Compositions of Aspirin

The present invention provides a method of increasing the bioavailability of clopidogrel, or a salt thereof or derivative thereof, in a subject. The method includes orally administering to the subject an effective amount of a composition comprising clopidogrel.

In one embodiment of the invention, according to standard pharmacokinetic practice, the clopidogrel / aspirin composition is about 50% larger, about 40% larger, about 30% larger, about 20% larger, than a conventional dosage form, Or about 10% greater bioavailability.

The compositions of the present invention are useful for the prevention and treatment of diseases caused by platelet aggregation. Pathological conditions include, but are not limited to, atherosclerosis or unstable angina, cerebral attack, angioplasty followed by restenosis, endarterectomy, or metallic endovascular prosthesis. thrombolysis following thrombolysis, infarction, dementia of ischemic origin, peripheral arterial disease related to diabetes, such as fitting of metallic endovascular prostheses Thromboembolism associated with hemodialyses, auricular fibrillation, or while using vascular prostheses or aortocoronary bypass, or with stable or unstable angors Cardiovascular and cerebrovascular diseases such as thromboembolic disorders. Preferably the compositions of the present invention are useful for the prevention and treatment of cardiovascular diseases.

The combination of clopidogrel and aspirin of the present invention, or salts or derivatives thereof, is not limited, but it is oral, rectal, eye, parenteral (eg, intravenous, intramuscular, or subcutaneous), intranasally It can be administered to a subject via conventional methods, including, by lungs, vaginally, intraperitoneally, topically (eg, powders, ointments or drops), or oral or nasal sprays. When the term "object" is used herein, it means an animal, preferably a human or mammal except human. The terms patient and object may be used interchangeably.

Compositions suitable for parenteral injection will include physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Can be. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propylene glycol, polyethylene-glycol, glycerol, and equivalents thereof), suitable mixtures thereof, vegetable oils (such as olive oil), and Injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

In addition, the combination of nanoparticulate clopidogrel and aspirin, or salts or derivatives thereof, may comprise adjuvant such as preservatives, humectants, emulsifiers, and dispensing agents. Blocking microbial growth can be maintained by various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid, and equivalents thereof. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and equivalents thereof. Prolonged absorption of injectable pharmaceutical formulations can be obtained by the use of agents that delay absorption such as aluminum monostearate and gelatin.

Solid dosage forms for oral administration include, but are not limited to, capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active agent is mixed with one or more of the following components: (a) one or more inert excipients (or carriers), such as sodium citrate or dicalcium phosphate; (b) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; (c) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (d) humectants, such as glycerol; (e) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain composite silicates, and sodium carbonate; (f) solution retarders such as paraffin; (g) absorption accelerators, such as quaternary ammonium compounds; (h) humectants, such as cetyl alcohol and glycerol monostearate; (i) adsorbents such as kaolin and bentonite; And j) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. For capsules, tablets, and pills, the dosage form may also include a buffer.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. Liquid dosage forms can include clopidogrel and aspirin as well as inert diluents, solubilizers, and emulsifiers commonly used in the art, such as water or other solvents. Representative emulsifiers are ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, cottonseed oil, peanut oil, corn germinated oil, olive oil, caster Oils, and oils such as sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycol, fatty acid esters of sorbitan, or mixtures of these materials, and equivalents thereof.

In addition to the inert diluents, the compositions may also include adjuvant such as moisturizers, emulsifiers and suspending agents, sweetening agents, flavoring agents, and fragrances.

In the "therapeutically effective amount" as used herein in the context of the combination of clopidogrel and aspirin, the dosage is administered to provide a specific pharmacological response when the combination of clopidogrel and aspirin is administered to a significant number of subjects in need of such treatment. Will mean quantity. Although such dosages are considered to be "therapeutically effective amounts" by those skilled in the art, it is noted that in certain embodiments a "therapeutically effective amount" administered to a particular subject will not always be effective in treating the diseases described herein. It should be emphasized. In certain instances it should be understood that the combined dose of clopidogrel and aspirin is measured by oral dose or by reference to drug levels measured in the blood.

Those skilled in the art will appreciate that the effective amount of the combination of clopidogrel and aspirin can be determined experimentally and can be used in pure form, or in the form of pharmaceutically acceptable salts, esters or prodrugs when pure form is present. Substantial levels of administration of the combination of clopidogrel and aspirin in the nanoparticulate compositions of the invention can be varied to obtain a content of the combination of clopidogrel and aspirin that is effective for obtaining the desired therapeutic response for the particular composition and method of administration. Therefore, the level of administration chosen depends on the desired therapeutic effect, the route of administration, the potency of the combination of administered clopidogrel and aspirin, the desired duration of treatment, and other factors.

Dosage unit compositions can include a submultiple of that content so that it can be used to supplement a daily dose. However, the specific degree of administration for a particular patient may include the type and degree of cellular or physiological response to be achieved; The activity of the specific drug or composition employed; The specific drug or composition used; The age, body weight, general health, sex and food intake of the patient; Time of administration, route of administration, and rate of drug release; Duration of treatment; Drugs used in combination or coincidental with the specific agent; And equivalent factors well known in the medical arts.

The following examples are provided to illustrate the present invention. However, the spirit and scope of the present invention is not limited by the specific conditions or details described in the examples, but only by the scope of the claims that follow. All references incorporated herein by reference, including US patents, are incorporated by reference.

Example  One

The purpose of this example is to describe how nanoparticle clopidogrel / aspirin combinations can be prepared.

Aqueous dispersions of clopidogrel bisulfate are combined with one or more surface stabilizers and, together with 500 micron PolyMill® attrition media (Dow Chemical) (89% medium loading), NanoMill® 0.01 (NanoMill Systems, Milling in a 10 ml chamber of King of Prussia, PA; see, eg, US Pat. No. 6,431,478. The composition can be milled at a speed of 2500 for a suitable time period, such as about 60 minutes.

The milled composition can be recovered and analyzed through a microscope. Microscopy can be performed using, for example, a Lecia DM5000B microscope and a Lecia CTR 5000 light source (Laboratory Instruments and Supplies Ltd., Ashbourne Co., Meath, Ireland). The microscope can show the presence of clopidogrel nanoparticles in the isolated state.

The particle size of the milled clopidogrel particles can also be measured in Milli Q Water using a Horiba LA-910 Particle Sizer (Particular Sciences, Hatton Derbyshire, UK). Compositions having a D50 particle size of less than about 2000 nm met the criteria of the present invention.

The particle size was measured in the initial state and 60 seconds after sonication. Significantly varying particle sizes after sonication are undesirable because this indicates the presence of clopidogrel aggregates. The agglomerates are the result of compositions having highly variable particle sizes. Such highly variable particle sizes can produce variable absorption between administration of the drug, which is undesirable.

The resulting nanoparticulate clopidogrel composition can be combined with conventional aspirin, microcrystalline aspirin, or nanoparticulate aspirin.

It will be apparent to those skilled in the art that various modifications and variations can be made to the methods and compositions of the present invention without departing from the spirit or scope of the invention. Accordingly, the present invention includes such modifications and variations provided that such modifications and variations are within the scope of the appended claims and their equivalents.

Claims (28)

(a) clopidogrel, or a salt or derivative thereof, having an effective average particle size of less than about 2000 nm; (b) aspirin, or salts thereof or derivative particles thereof; And (c) A composition of stable nanoparticulate clopidogrel and aspirin comprising at least one surface stabilizer. The composition of claim 1, wherein the nanoparticulate clopidogrel is clopidogrel bisulfate. The group of claim 1, wherein the clopidogrel particles, the aspirin particles, or a combination thereof are composed of a crystalline phase, an amorphous phase, a semi-crystalline phase, a semi amorphous phase, and a mixture thereof. The composition is selected from. The composition of claim 1, wherein the aspirin particles have an effective average particle size of less than about 2000 nm. The method of claim 1, wherein the effective average particle size of the clopidogrel particles, the aspirin particles, or both the clopidogrel particles and the aspirin particles is less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, less than about 1600 nm, about Less than 1500 nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm, less than about 1100 nm, less than about 1000 nm, less than about 900 nm, less than about 800 nm, less than about 700 nm, less than about 600 nm, about The composition is selected from the group consisting of less than 500 nm, less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about 200 nm, less than about 100 nm, less than about 75 nm, and less than about 50 nm. The composition of claim 1, wherein the clopidogrel particles have improved bioavailability compared to conventional clopidogrel tablets. The method of claim 1, wherein the composition (a) Administration selected from the group consisting of oral, pulmonary, rectal, colon, parenteral, intracranial, intravaginal, intraperitoneal, eye, ear, local, oral, nasal, and topical administration. Formulated for; (b) in a dosage form selected from the group consisting of liquid dispersions, gels, aerosols, ointments, creams, lyophilized preparations, tablets, and capsules; (c) controlled release formulations, fast melt formulations, delayed release formulations, extended release formulations, pulsatile release formulations, and immediate release formulations. ) And a dosage form selected from the group consisting of a controlled release release formulation; (d) a composition which is formulated in a combination of (a), (b) and (c). The composition of claim 1, wherein the composition further comprises one or more pharmaceutically acceptable excipients, carriers, or a combination thereof. The method of claim 1, (a) the clopidogrel, the aspirin, or a combination thereof, does not include other excipients, to the total combined dry weight of clopidogrel, aspirin, or a combination thereof, and one or more surface stabilizers, respectively. Relative to about 99.5 wt% to about 0.001 wt%, about 95 wt% to about 0.1 wt%, and about 90 wt% to about 0.5 wt%; (b) about 0.5% to about 99.999% by weight, relative to the total dry weight of clopidogrel, aspirin, or a combination thereof, and one or more surface stabilizers, wherein the one or more surface stabilizers do not include other excipients 5.0 wt% to about 99.9 wt%, and about 10 wt% to about 99.5 wt%; or (c) The composition is a combination of (a) and (b). The group of claim 1 wherein the surface stabilizer is a group consisting of a nonionic surface stabilizer, anionic surface stabilizer, cationic surface stabilizer, zwitterionic surface stabilizer, and ionic surface stabilizer The composition selected from: The method of claim 1, wherein the surface stabilizer is cetyl pyridinium chloride, gelatin, casein, phosphatide, dextran, glycerol, gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, Glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acids Esters, polyethylene glycols, dodecyl trimethyl ammonium bromide, polyoxyethylene stearate, colloidal silicon dioxide, phosphate, sodium dodecyl sulfate, carboxymethylcellulose calcium, hydroxypropyl cellulose, hypromellose, Carboxymethylcellulose Sodium, Methyl 4- (1, with cellulose, hydroxyethylcellulose, hypromellose phthalate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, polyvinylpyrrolidone, ethylene oxide and formaldehyde 1,3,3-tetramethylbutyl) -phenol polymer, poloxamer; Poloxamine, charged phospholipid, dioctylsulfosuccinate, dialkyl ester of sodium sulfosuccinic acid, sodium lauryl sulfate, alkyl aryl polyether sulfonate, a mixture of sucrose stearate and sucrose distearate, p Isononylphenoxypoly- (glycidol), decanoyl-N-methylglucamide; n-decyl β-D-glucopyranoside; n-decyl β-D-maltopyranoside; n-dodecyl β-D-glucopyranoside; n-dodecyl β-D-maltoside; Heptanoyl-N-methylglucamide; n-heptyl-β-D-glucopyranoside; n-heptyl β-D-thioglucoside; n-hexyl β-D-glucopyranoside; Nonanoyl-N-methylglucamide; n-noyl β-D-glucopyranoside; Octanoyl-N-methylglucamide; n-octyl-β-D-glucopyranoside; Octyl β-D-thioglucopyranoside; Lysozyme, PEG-phospholipid, PEG-cholesterol, PEG-cholesterol derivative, PEG-vitamin A, PEG-vitamin E, lysozyme, random copolymer of vinyl acetate and vinyl pyrrolidone, cationic polymer, cation Cationic Biopolymers, Cationic Polysaccharides, Cationic Cellulosics, Cationic Alginates, Cationic Nonpolymeric Compounds, Cationic Phospholipids, Cationic Lipids, Polymethylmethacrylate Trimethylammonium Bromide, sulfonium compounds, polyvinylpyrrolidone-2-dimethylaminoethyl methacrylate dimethyl sulfate, hexadecyltrimethyl ammonium bromide, phosphonium compounds, quaternary ammonium compounds, benzyl-di (2-chloroethyl) ethylammonium Bromide, coconut trimethyl ammonium chloride, coconut trimethyl ammonium bromide, coconut methyl dihydroxy Ammonium chloride, coconut methyl dihydroxyethyl ammonium bromide, decyl triethyl ammonium chloride, decyl dimethyl hydroxyethyl ammonium chloride, decyl dimethyl hydroxyethyl ammonium chloride bromide, C _{12 - 15} dimethyl hydroxyethyl ammonium chloride, C _{12 - 15} dimethyl hydroxyethyl ammonium chloride bromide, coconut dimethyl hydroxyethyl ammonium chloride, coconut dimethyl hydroxyethyl ammonium bromide, myristyl trimethyl ammonium methyl sulfate, lauryl dimethyl benzyl ammonium chloride, lauryl dimethyl benzyl ammonium bromide, lauryl dimethyl (when the tenok) ₄ ammonium chloride, referred to (not tenok a) lauryl dimethyl ammonium bromide _4, N- alkyl (C _{12 -18)} dimethyl benzyl ammonium chloride, N- alkyl (C _{14 -18)} dimethyl benzyl ammonium chloride, N-Tet Decyl dimethyl benzyl ammonium chloride monohydrate, dimethyl didecyl ammonium chloride, N- alkyl and (C _{12 -14)} dimethyl 1-naphthylmethyl ammonium chloride, trimethylammonium halide, alkyl-trimethylammonium salts, dialkyl-dimethylammonium salts , Lauryl trimethyl ammonium chloride, ethoxylated alkyl amidoalkyldialkylammonium salt, ethoxylated trialkyl ammonium salt, dialkylbenzene dialkylammonium chloride, N-didecyldimethyl ammonium chloride, N- tetradecyl dimethyl benzyl ammonium chloride monohydrate, N- alkyl (C _{12 -14)} dimethyl 1-naphthylmethyl ammonium chloride, dodecyl dimethyl benzyl ammonium chloride, dialkyl benzene alkyl ammonium chloride, lauryl trimethyl ammonium chloride, alkyl benzyl methyl ammonium chloride, alkyl benzyl dimethyl ammonium bromide, C ₁₂ bit Methyl ammonium bromide, C ₁₅ trimethyl ammonium bromides, C ₁₇ trimethyl ammonium bromide, dodecyl benzyl triethyl ammonium chloride, poly-diallyldimethylammonium chloride (DADMAC), dimethyl ammonium chloride, alkyl dimethyl ammonium halogenide arsenide, tri Cetyl methyl ammonium Chloride, decyltrimethylammonium bromide, dodecyltriethylammonium bromide, tetradecyltrimethylammonium bromide, methyl trioctylammonium chloride, POLYQUAT10 ^™ , tetrabutylammonium bromide, benzyl trimethylammonium bromide, choline esters, benzalkonium chloride, stear Alkonium chloride compounds, cetyl pyridinium bromide, cetyl pyridinium chloride, halide salts of quaternized polyoxyethylalkylamines, MIRAPOL ^™ , ALKAQUAT ^™ , alkyl pyridinium salts; A composition selected from the group consisting of amines, amine salts, amine oxides, imide azolinium salts, quantized quaternary acrylamides, methylated quaternary polymers, and cationic guar . The composition of claim 1, further comprising one or more active agents useful for the prevention and treatment of pathologies caused by platelet aggregation. The composition of claim 12, wherein the disease is a cardiovascular disease. 13. The method of claim 12, wherein the one or more active agents are calcium-entry blocking agents, antianginal agents, cardiac glycosides, vasodilators, antihypertensive agents, blood lipid-lowering agents, antiarrhythmic agents. , And an antithrombogenic agent. The composition of claim 1, wherein said composition does not produce significantly different levels of absorption when administered in a fed condition relative to a fasting condition. The composition of claim 1, wherein the administration of the composition to a fasting subject is bioequivalent to the administration of the composition to a subject in a fed state. The method of claim 1, wherein the composition (a) the administration after analyzing in plasma of a mammal object of clopidogrel, or a salt thereof, or with a C _max of a derivative thereof administered in the same dose the same clopidogrel, or a salt thereof or a derivative thereof non-nanoparticle-type (non-nanoparticulate ) Greater than the C _{max of the} formulation; (b) the AUC of clopidogrel, or a salt or derivative thereof, analyzed in the plasma of a mammalian subject after administration is greater than the AUC of a non-nanoparticulate formulation of the same clopidogrel, or a salt or derivative thereof, administered at the same dose Greater than; (c) the administration after analyzing in plasma of a mammal object of clopidogrel, or a salt thereof, or a derivative T _max is the ratio of the same clopidogrel, or a salt or a derivative thereof administered in the same dose-type nanoparticle formulation T _max Smaller than; or (d) The composition is a combination of (a), (b), and (c). A controlled release pharmaceutical composition comprising the combination composition of clopidogrel and aspirin of claim 1, wherein the clopidogrel particles, the aspirin particles, or a combination thereof are covered with at least one polymeric coating layer. Pharmaceutical composition. A controlled release pharmaceutical composition comprising the combination composition of clopidogrel and aspirin of claim 1, wherein the particles are incorporated into a polymeric matrix. The composition of claim 1, further comprising an enteric coating covering the clopidogrel particles, the aspirin particles, or a combination thereof. (a) contacting clopidogrel, or a salt thereof or derivative thereof, with one or more surface stabilizers for a time and under conditions sufficient to provide a nanoparticulate clopidogrel composition having an effective average particle size of less than about 2000 nm; And (b) combining the resulting nanoparticulate clopidogrel with aspirin, or a salt or derivative thereof, to prepare a nanoparticulate clopidogrel and aspirin combination. A method of oral clopidogrel and aspirin combination comprising administering the composition of claim 1 to reduce irritation of the stomach and / or esophagus, minimize solubilization of clopidogrel and reduce precipitation of clopidogrel. (a) clopidogrel, or a salt or derivative thereof, having an effective average particle size of less than about 2000 nm; (b) one or more surface stabilizers; And (c) A stable nanoparticulate clopidogrel composition comprising an enteric coating surrounding said clopidogrel particles. A method of administering oral clopidogrel, comprising administering the composition of claim 23, to reduce irritation of the stomach and / or esophagus, minimize solubilization of clopidogrel, and reduce precipitation of clopidogrel. (a) clopidogrel, or a salt or derivative thereof; And (b) a composition comprising an enteric coating surrounding the clopidogrel to inhibit release of the clopidogrel in the stomach. The method of claim 25, wherein the amount of clopidogrel released over the subject is about 0.05% or less, about 0.5% or less, about 1% or less, about 5% or less and about 10% or less relative to the total dose administered to the subject. The composition is selected from the group consisting of. The method of claim 25, wherein the amount of clopidogrel released from the intestine of the subject is from a group consisting of at least about 90%, at least about 95%, at least about 97% and at least about 100% relative to the total dose administered to the subject. The composition selected. A method of administering oral clopidogrel, comprising administering the composition of claim 25, to reduce irritation of the stomach and / or esophagus, minimize solubilization of clopidogrel, and reduce precipitation of clopidogrel.